Biopharmaceutics
It is the relationship between physicochemical properties of drug substance and its delivery system to its
absorption into the systemic circulation when taken by all route of administration except I.V route.
Absorption
▪
▪
▪
Distribution
▪
▪
▪
▪
Volume of distribution
▪
Considered with only orally administration and absorption for GIT.
This phase is irreversible as if drug absorbed from GIT to blood, it won’t return back against
to GIT.
Distribution will be in equilibrium state as after absorption, drug distributed within blood,
body fluids and tissues always in equilibrium
This phase is reversible as if drug cab be transported from blood into tissues or reverse to
attain the body in complete equilibrium
Example: The concentration of mepacrine in liver to plasma at distribution equilibrium is
25000: 1 ‫امتحااااااااااااااااااااان‬
This phase is irreversible
Elimination done by major routes and some minor routes:
Minor elimination routes (5%)
Elimination ▪ Lung excretions
▪ Skin excretions
▪ Excretion by saliva
▪ It is a parameter shows the relative amount of drug outside blood (in tissue)
amount of drug in body
Volume of distripution =
Cpo
o
▪ If Cp increases → Vd decreases → drug localized in blood
▪ If Cpo decreases→ Vd increases → drug localized in tissue
❑ Significance of determining Vd: ➢ Detection of tissue localization as:
1- Drugs with high lipid solubility (non-polar) or has low ionization rates → localized in tissues
2- Drugs with high water solubility (polar) or has high ionization rates→ localized in Blood
Tubocurarine
▪
▪
▪
▪
Mepacrine
Muscle relaxant
Have short T1/2
Have high water solubility → drug localized
in blood
By increasing Cpo → Vd decreases
▪
▪
▪
▪
Have long T1/2
Have High lipid solubility → drug localized in tissues
By decreasing Cpo → Vd increases
Its conc. In tissue is 25.000 times its conc. in plasma
A. ABSORPTION PHASE
Major elimination routes (95%)
Composition of biological membrane:
▪ Urinary excretion
▪ Liver metabolism (biotransformation)
1) Lipids
➢ Glycero lipid
➢ Neutral lipid
➢ Phospho lipids (phosphatidyl serine, phosphatidyl choline, phosphatidyl ethanolamine)
2) Protein
3) Lipoprotein
4) Polysaccharide
• Only phospholipid has the important role of absorption. ‫امتحان‬
•
•
•
Gastrointestinal membrane act as lipoidal sieve which allow passage of lipid soluble drugs and prevent
passage of water-soluble drugs.
If the drug is completely lipid soluble without any water solubility it will not absorbed
The drug must be lipid soluble with slightly water solubility.
Biological factors
Mechanisms of drug absorption
1) Passive diffusion
Pharmacokinetics
Bioavailability
Absolute bioavailability
Relative bioavailability
Half life
Drug disposition
Tissue localization
▪ Rate process of absorption, distribution, metabolism and elimination of
drug.
▪ It is the rate and extent of absorption of an administered dose into
systemic circulation given by all routes except I.V route
▪ in which we compare any route of administration with I.V route
▪ in which we compare any route of administration to each other e.g.
(rectal to oral, transdermal to oral) or different dosage form to each
other e.g. (cap.to tablet, syrup to tab)
▪ It is the time needed for drug to decline to its half of initial concentration
at any given time
▪ Loss of drug from blood compartment due to distribution to other tissues
and elimination phase.
▪ Selective uptake of drug into the tissue or affinity in localization in certain
tissues.
• Drug transfer along concentration Gradient i.e. From high conc. to low conc.
• Follow Fick’s low of diffusion
Fick’s law:
•
Rate of diffusion across membrane is directly proportional to difference in drug
conc. On both side of membrane
𝛥𝐶
−
= 𝐾𝑎 [𝐶1 − 𝐶2 ]
𝛥𝑡
Where:
𝛥𝐶
𝛥𝑡
is rate of diffusion
Ka is diffusion constant (proportionality constant)
C1 is the concentration outside the
C2 is the concentration inside the membrane
Diffusion is affected by:
1- Thickness of the membrane as decreasing thickness will increase the diffusion
2- Area of the membrane as increasing surface area will increase the diffusion
3- Diffusion coefficient of drug
𝛥𝐶
In body: − = 𝐾𝑎 [𝐶1 ]
𝛥𝑡
2)Active diffusion
▪
1- Size of pores & molecules
2- Solvent drag  by increasing of water influx, absorption increase
3- Conc of drug in the intestinal lumen as by increasing conc.  the probability of presence of drug
adjacent to pores of mucosa increase  pore transport increases
Highly water-soluble material is very difficult to be absorbed in GIT which consist of lipid, so this method is
important for transfer of essential substances as - Amino acid - glucose.
Characters of active transport:
o
o
o
o
o
o
Physiological factors
Particles moves against concentration gradient (from low conc. To high conc)
Carrier mediated transport (depend on carriers for transport)
Saturable process (saturation of carriers occurs as the number of carriers in fixed).
Site specificity  as carriers located only in the upper part of the small intestine  no carriers in stomach,
colon, large intestine.
Structure specificity  each carrier is specific for certain molecule (i.e. carrier searches for specific structure
for binding).
Competitive process  when more drugs have the same groups, competition on carriers will occur
Energetic process  i.e. needs energy  affected by metabolite inhibitors such as anoxia (lack of oxygen),
fluorides, dinitrophenol
Not affected by pH or surface area
Cannot be used by rectal route (ex. suppository)
Follows zero order kinetics the absorption increases till all carriers are consumed and extra increase leads
to stopping of the absorption
Active transport  Zero order kinetics  absorb fixed amount
passive transport  First order kinetics  absorb fixed percent
Anatomy of GI
tract
Physiological Factors
Affacting Drug
Absorption
o
o
o
o
Example:
o In treatment of diarrhea, we use glucose in concentration of 5%, if the concentration increased to 50-60%,
only 5% will be absorbed and the excess amount will be concentrated in large intestine and dissolve in water
causing more diarrhea.
pH of GI tract
Food
volume of food
Temperature of food
body posture
Gatric emptying
rate
Viscosity
Diatery Effect
Drugs
Intestinal Motility
Acidity
Drug Stability in
GI tract
Hepatic
Metabolism
particle size
Emotional state
Local disease
GastricSurgery
Diarrhea
Micellaneous
Age
3)Facilitated diffusion
Stress
The same as active transport but differs in:
▪ Drug transfer along conc. Gradient and Not require energy
Examples: Quaternary ammonium compounds and Vitamin B12 ‫مهم‬
Bed ridden patient
4) Ion Pair Mechanism
Unionized form  lipid soluble  absorbed
Ionized form  water soluble  not absorbed
▪ Each ion attached to membrane another ion of the opposite charge
in the GIT to form neutral ion (ion pair) which have high lipid
solubility so can pass gastrointestinal mucosa.
Quaternary ammonium compounds and tetracycline: ‫مهم جدا‬
▪ These drugs are highly ionized in the GIT so lipid insoluble and not
absorbed
▪ They are too large molecules to pass through pores of the cell
membrane of GIT but it found that these drugs can pass in large
amounts due to ion pair mechanism.
▪ There in a drug interaction with endogenous materials or organic ions of opposite charges forming neutral
ions with high lipid solubility.
5)Pinocytosis = phagocytosis
▪
▪
▪
▪
Drug molecules not have to be in solution to be absorbed.
It is important for absorption of macro molecules by engulfing ex: protein
It’s specialized for absorption of Macromolecules (large M.wt.) as: (Fats, proteins, vitamins A, D, E)
It is essential for absorption of milk protein in infants.
6) Pore transport
▪
Size of the radius of aqueous field pores is 4Ao so drugs which have this molecular size or less, can be absorbed
by pore transport.
▪ Examples  Urea, H2O and low molecular weight sugars.
Factors affecting absorption by ore transport:
1. Anatomy of GIT
•
•
•
Stomach
Small intestine, subdivided to (Duodenum, jejunum and ileum)
Large intestine
❑ Small Intestine:
➢ Small intestine is the main site of absorption as: ‫مهم‬
a. It has a large surface area due to presence of villi (finger like projection) which increase surface area of
absorption millions of time rather than normal cylinder.
b. It is the longest part of GI tract.
c. Exhibit a long residence time.
Length of Various region of GI tract
Overall length of GI tract
Small intestine (duodenum, jejunum and ileum)
Large intestine
About 4.5 meter
About 2.75 meter
1 meter
Physiological conditions of GIT
Part
Residence time
Mouth & Esophagus
Stomach
Small intestine
Large intestine
Few minutes
0.5 – 3 hours
6 – 8 hours
10 hours
PH
Secretions
5 – 8.5
1 – 1.5
7.5 – 8.5
No secretions
Chyme
No
3–5
6–8
7 – 7.5
Absorption area
(Meter2)
No
0.1 – 0.2
100
0.5 – 1
2. pH of the GIT
Emotional
state
pH of Stomach → about 1 – 1.5 pH of duodenum → about 5.5 – 6.5 pH of colon → about 7 – 7.5
pH is about 1 – 1.5
Fasting
pH increases after meal so absorption decreases
Fats in food
Anticholinergic
Decrease the secretion of HCL so pH increases
Antispasmodic
Antacids
Increase the pH by Neutralizing acidity of the stomach
Peptic ulcers
increase the secretion of HCL so pH decreases
•
•
Acidity
‫مهم جدا جدا‬
•
The stomach empties its contents into the small intestine. Because the duodenum has the greatest capacity
for the absorption of drugs from the GIT, a delay in the gastric emptying time for the drug to reach the
duodenum will slow the rate and possibly the extent of drug absorption, thereby prolonging the onset time
for the drug.
• Generally, we prefer rapid gastric emptying rate‫مهمة جدا‬
Repulsive Movement
5 mg
10 mg
30 mg
2.4 mg
3 mg
4.7 mg
Absorption after meals
3.1 mg
6.3 mg
18.2 mg
Effect of food on Griseofulvin
Increased % of
absorption
29 %
110 %
287%
•
When taken with fatty meals, GER decreased and absorption increased as it makes contraction of gall
bladder which make stimulation of secretion of bile which increase emulsification of fats so increased
absorption
• They found that griseofulvin when taken with fatty meals, its concentration in blood is 8 times more
than if taken before meals.
❑ Factors affecting GER:
Food
•
Volume of the •
•
food
Temperature
of food
Body posture
Viscosity
•
•
•
•
•
•
Food (fat, protein and carbohydrate) decreases GER
Fat > Protein > Carbohydrate
Small volumes → initial lag time of GER is slow, then become rapid.
Large Volumes → initial lag time of GER is rapid, then become slow.
Temp up to 37 oC → GER increased.
Temp above 37 oC → GER decreased.
In case of hot meals, GER is decreased as a protective reflex mechanism occur to
protect duodenum cells which cause contraction of sphincter to prevent passage of
food to delay GER.
Lying on the right side enhance the GER more than the left side.
Increasing viscosity will decrease GER
Decreasing viscosity will increase GER
Duodenal ulcers
Reflex action will be low as duodenal
contents are acidic and cannot
differentiate between acidic drugs and its
contents so it will increase GER
Circular (mixed) Movement
•
Contraction occurs longitudinally by longitudinal •
muscles
•
• Can affect Transit time and residence time.
• Hypermotility (increasing motility) decreases •
residence time and absorption.
• Hypomotility (decreasing motility) increase
residence time and absorption.
Contraction occurs due to circular muscles.
Affects increasing dissolution rate of poorly
soluble drugs.
Allow drug molecules to leave chyme and
contact with intestinal mucosa so increase
absorption.
❑ Importance of intestinal residence:
➢ It is important for:
1) drugs absorbed by intestinal carrier mediated active transport mechanism.
2) sustained and prolonged release formulations.
3) Enteric coated formulations.
4) Drugs dissolves slowly in the intestinal fluids.
Effect of food on Riboflavin
Absorption in fasting state
Hyperacidity stimulate the GER
Achlorhydria decreases the GER
Peptic ulcers
Firstly, increasing acidity will increase the
GER but excessive increasing cause reflex
mechanism which leads to contraction of
sphincter to protect duodenal cells from
high acidity leading to decrease GER
4. Intestinal Motility
Rapid gastric emptying rate is preferred in Slow gastric emptying rate is preferred in
Dose
Excitation will increase GER due to increasing GIT motility.
Depression will decrease GER due to decreasing GIT motility.
Particle size • Fine particles increase GER while coarse particles decrease it
Effect of drugs • Antacids, antispasmodics and anticholinergics decrease GER
3. Gastric Emptying rate
1- Drugs that are unstable in stomach as 1. Active transport as riboflavin (vitamin B2) if
erythromycin and benzyl penicillin.
taken in empty stomach → their absorption will ↓
2- Enteric coated formulations.
so they are better absorbed when taken after meals
3- Anthelmintic drugs  to optimize the
2. Lipid soluble drug as Griseofulvin If taken with
therapeutic effect.
fatty meals → its bioavailability will be enhanced.
4- Anti-amoebic drugs
Why? As with fatty meals the biliary secretion
5- Basic drugs.
occur which enhance absorption of the lipid soluble
6- Drugs that are irritant to stomach.
drugs so slow gastric emptying rate is required to
allow the biliary secretions to take place
•
•
5. Drug Stability in GI Tract and Interaction of Drug with
Components of GI Tract
•
•
Mucin → is Viscous mucopolysaccharide acts as protective layer that covers the mucosae of stomach and
intestine.
Enzymes may convert prodrugs to active metabolites as:
𝐸𝑠𝑡𝑒𝑟𝑎𝑠𝑒 𝑒𝑛𝑧𝑦𝑚𝑒
Acetoxy methyl ester of penicillin →
penicillin
𝐸𝑠𝑡𝑒𝑟𝑎𝑠𝑒 𝑒𝑛𝑧𝑦𝑚𝑒
•
•
Chloramphenicol palmitate →
chloramphenicol
Enzymes may convert drug in the active form to inactive form
as insulin by enzymatic hydrolysis gives amino acids that is inactive
Drugs may be hydrolyzed in the GIT by:
6. Hepatic Metabolism
Physico chemical factors
affect drug absorption
❑ first pass effect:
•
Drugs which absorbed from the GI tract always pass in hepatic portal vein before reaching blood so liver
degrades part of drug.
❑ Solution for first pass effect:
PH partition
theory
a. Give the drug by another route than oral route such as injection, suppositories or inhalation.
b. Increase the oral dose
c. Increase dissolution rate of the drug
Dissolution
rate
Complexation
Adsorption
Surface active
agent (SAA)
❑ N.B.
•
•
If we increase oral dose, molecules that received by liver will be exceed the capacity of liver enzymes so some
will be broken by liver and other will pass unchanged.
If we intended to use rectal suppositories, administration must be in lower part of rectum.
1- pH Partition Theory
❑ It is a relationship between:
➢ the dissolution constant of drug
➢ lipid solubility for drug
➢ pH of the absorption site
Example:
Isoprenaline (Antiasthmatic)
Route
Dose
Injection
200 µg/ml
Inhalation
80 µg/ml
Oral
30000 µg/ml
7. Dietary Food
•
•
Generally, gastrointestinal absorption is Preferred by an empty stomach
The effect of food on the absorption rate of drugs is probably result of delay in the GER and decrease
bioavailability.
• Alteration in the rate of gastric emptying especially (solid - hot - fatty) meals so delay gastric emptying and ↓
bioavailability of drug
• Cellulosic food with high viscosity may absorb some drugs so decrease the absorption of these drugs.
• Tetracycline when taken with antacids (contains Ca+2 or Mg+2) or dietary products containing calcium or
iron ions, it will form non-absorbable complex.
• Bile acids may form insoluble non-absorbable complex with neomycin, nystatin and kanamycin.
• The absorption of few drugs is actually promoted when administered following a meal for example
Griseofulvin, its absorption increases with fatty meals. ‫مهمة‬
• After meals, blood flow to liver and GI tract increase leading to increasing absorption rate.
• Gastric secretions may increase the absorption of drugs that is stable in acidic pH, on the other hand, it
decreases the absorption of the unstable drugs.
• Fats stimulate secretion of bile → so ↑ rate of dissolution of lipid soluble drugs and ↑ bioavailability
❑ Henderson-Hasselbalch equation:
For Acidic drugs
pKa − pH = log
•
Gastric surgery
Diarrhea
Age
Stress
Bed ridden
•
•
•
•
•
•
•
•
•
Cause alteration of the gastric pH
pH elevates to 6.9 or 7 with gastric cancer
total or partial gastrectomy
if drugs slowly dissolute, absorption decreases and bioavailability decrease.
If drugs rapidly dissolute to small intestine, it will increase its GER, absorption and
bioavailability.
Hypermotility leads to decrease of residence time so absorption decreases.
Increasing age will decrease absorption
Stress will decrease absorption.
Decrease absorption.
Physicochemical Factors Affecting Drug
Absorption
Ci
Cu
Cu=concentration of ionized fraction
pKa − pH = log
•
❑ Examples:
•
•
•
•
•
2 Acidic drugs
Drug A with pKa 5
Drug B with pKa 10
Drug A is more acidic than drug B so drug A is •
more ionized than drug B so drug B is more
absorbed.
•
•
2 Basic drugs
Drug A with pKa 5
Drug B with pKa 10
Drug B is more basic than drug A so drug B is
more ionized than drug A so drug A is more
absorbed.
pKa of basic drug & pKa of acidic drugs →  ionization → absorption
For acidic drugs, High pKa means weak acid so less ionized and highly absorbed
For basic drugs, High pKa means strong acid so more ionized and poorly absorbed
Drugs with PKa 1 or 2 will be strongly acidic and in ionized form then absorption decreased.
Drugs with PKa 13 or 14 will be strongly basic and in ionized form then the absorption
decreased
❑ Partition coefficient:
8. Miscellaneous factors
Local disease
Cu
Ci
Cu=concentration of unionized fraction
For basic drugs
Barbiturates absorption in rat colon
is defined as the ratio of the concentration of a
solute in the organic solvent or lipid phase to its
concentration in the water phase.
By increasing Partition coefficient, absorption
increases
conc. of drug in lipid
partition coefficient =
conc. of drug in water
Drug
Barbital
Phenobarbital
Cyclobarbital
Pentobarbital
Secobarbital
Partition
coefficient
0.7
4.8
13.9
28
50.7
%
absorbed
12
20
24
30
40
2- Dissolution Rate
• When a drug is given orally, the rate of absorption is often controlled by how fast the drug
dissolves in the absorption site.
𝑑𝑖𝑠𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛
𝑎𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛
Solid drug →
drug solution at absorption site →
• Absorption of different dosage forms:
drug in systemic circulation
•
•
To improve the dissolution of Acidic drugs in acidic medium, we formulate the drug in its Basic salts.
And for Basic drugs in alkaline medium we formulate it in its Acidic salt as:
a. Atropine → Atropine sulphate
b. Codeine → Codeine phosphate
Salt Formation
❑ Aluminum salt of aspirin:
•
Aluminum salts of aspirin is used for showable tablets to
minimize the taste of the drug but unfortunately it is more
slowly absorbed.
• At pH 8, dissolution rate decreased due to formation of basic
insoluble Al (OH)3 upon reaction with water.
• Al (OH)3 is insoluble gelatinous form that retard penetration
of water so take long time for disintegration and dissolution
decreased.
• To solve this problem, Adding EDTA as chelating agent to
chelate free Al ions to prevent formation of Al (OH)3
Generally, we prefer high dissolution rates for drugs.
❑ Drugs requires slow dissolution rates:
o Irritant drugs as nitrofurantoin.
o Unstable drugs as erythromycin and benzyl penicillin.
❑ Factors affecting dissolution rate of drugs:
a)
b)
c)
d)
Noye’s and Whitney equation.
Crystallization
Surface area.
Hydration and solvation
a) Noye’s and Whitney equation
dC DSCs
=
dt
h
▪
•
•
•
• For example: Acidic drug (Salicylic acid)
Solution:
• Addition of nahco3 to the salicylic acid, it will
result in the formation of Na. Salicylate and
increase PH of the diffusion layer leading to
enhancement of the dissolution of salicylic acid.
• Once Na. Salicylate diffuse to the bulk, it will react
with HCL → and predicated as very fine particles in very huge surface area which enhance diffusion →
become ready for absorption
•
•
•
For basic drugs
•
•
•
Particle size → surface area → rate of dissolution →rate of absorption.
❑ Types of Surface Area:
Effective surface area
❑ Solubility in the diffusion layer and salt formation:
•
decrease hydrogen ion conc and increase dissolution so drug transfer from diffusion layer to bulk
(stomach) where it precipitates as fine particles so increasing of surface area will increase dissolution
b) Surface Area
Where:
▪ dc/dt → is the dissolution rate.
▪ K → dissolution rate constant (equals D/h)
▪ D→ is the diffusion coefficient of the dissolving material
▪ h → the thickness of the diffusion layer (membrane)
▪ S → surface area of the dissolving solid.
▪ Cs → is the saturation solubility of the drug in solvent.
▪ C → concentration of drug in the solvent at time t
•
1.7
1870
< 0.1
550
• Salicylic acid will decrease dissolution rate so by adding NaHCO3, it will give Na. salicylate which
In body:
▪ The C is negligible compared to Cs, so equation can be written as:
dc
Ka
= K’Co [1 + + ]
[H ]
dt
Rate of dissolution is inversely proportional to
hydrogen ion concentration.
hydrogen ion conc. (pH) →dissolution rate.
pH of the stomach is about (1-2) so increasing H+
ion conc will decrease the dissolution rate and the
rate of absorption also decreases.
To solve this problem, we should decrease H+ ion
conc by salt formation
Benzoic acid
Sodium benzoate salt
Phenobarbital
Sodium
phenobarbital salt
Salicylic acid
Sodium salicylate salt
Sulfathiazole
Sodium sulfathiazole
salt
Dissolution
rate at pH 1-2
2.1
980
0.24
200
Buffering system
dC
DS(Cs − 𝐶)
= KS(CS − C) =
dt
h
For acidic drugs
Compound
[H + ]
dc
= K’Co [1 +
]
dt
Ka
Rate of dissolution is directly proportional to
hydrogen ion concentration.
hydrogen ion conc. (pH) →dissolution rate.
pH of the stomach is about (1-2) so increasing H+
ion conc will increase the dissolution rate and the
rate of absorption also decreases.
But stomach not the good site for absorption of
basic drugs so when dissolution rate of basic drugs
increases in stomach, this increases the absorption
of these drugs in intestine.
Specific (absolute) surface area
It is the surface area of drug in body.
•
It is the surface area of solid surface that •
exposed to the dissolution medium.
It is less than specific surface area.
•
It is the surface are of drug measured in labs.
It is the total surface area of solid surface of any
particle.
It is more than effective surface area.
❑ Effect of surface area on griseofulvin:
Effect of particle size on dissolution rate of Griseofulvin
•
•
•
GROUP
DOSE
PARTICLE SIZE BLOOD LEVEL
Group 1
1g
10 µ
Drug Blood conc is
equal
Group 2
0.5 g
2.5 µ
The experiment was done on 2 different groups of experimental animals.
Each group received a different dose with different particle size of griseofulvin.
The observed result was that both drug blood conc of drug is equal in the two groups however there was a
difference in the administered dose.
❑ Effect of surface area on Chloramphenicol:
•
•
•
•
Chloramphenicol exists in three doses with different particle sizes (50, 400, 500).
The three doses have the same extent of absorption and the
same bioavailability, but differs in the residence time.
They have different plasma peak (conc time curve) but have
the same AUC (bioequivalent).
The more residence time will affect the beneficial normal
flora in the GI tract, so we should decrease residence time
to prevent effect on normal flora, so increasing the
dissolution rate is a must. ‫مهم جدا‬
 Residence Time →  Effect on Normal Flora
c) Polymorphism
▪
It is the presence of substance in more than one crystalline form.
▪
▪
•
•
Amphetamine + CMC (carboxymethyl cellulose) → give non-absorbable complex.
Phenobarbital + PEC 4000 (polyethylene glycol) → give non-absorbable complex.
• Tetracycline + heavy metals (Ca+2, Mg+2, iron)→ give non-absorbable
Polymorphism includes Amorphous and crystalline state.
They may differ in:
1. Density,
2. Melting point,
3. Solubility,
4. Dissolution rate.
Amorphous
4- Adsorption
❑ Types of Adsorption:
Crystalline
Metastable form (unstable)
Stable form
• Highest energy state
• Lowest energy state
• Lowest melting point
• Highest melting point
• Higher solubility
• Lower solubility
• Active form
• Inactive form
• Better absorption and bioavailability.
• Lower bioavailability
❑ Conversion between amorphous and crystalline:
▪ Amorphous form which is active form, may be converted to inactive crystalline form so we can prevent this
conversion by addition of methyl cellulose as suspending agent
❑ Examples:
1- Insulin:
➢ Amorphous state → highly soluble so increases dissolution rate and give immediate action.
➢ Crystalline state → lower solubility so decreases dissolution rate and gives sustained action
2- Chloramphenicol & Novobiocin:
➢ Amorphous → active form with high absorption rate
➢ Crystalline → inactive form with low absorption rate
3- Riboflavin (Vit B2):
➢ Have 3 different polymeric forms that differ in dissolution rate and the range are from 60 to 1200
mg/l
d) Solvation and Hydration
▪
Crystallization of one molecule of substance combined with one or more molecule of solvent
➢ Hydrates → when the solvent is water.
➢ Solvates → when the solvent is Organic solvent.
❑ For Hydration:
Anhydrous form has greater dissolution rates that hydrous form.
Examples:
1. Ampicillin (anhydrous) and Ampicillin trihydrate
2. Mercaptopurine
❑ For solvation:
Solvated form has greater dissolution rates that A solvated form.
Examples:
1. Grisofalvin chloroformate (solvated form) and Grisofalvin (asolvated form)
3- Complexation
• Interaction of the drug with materials in GI tract or with inert or active compound of the
dosage form.
❑ Complexation may affect: ‫مهم جدا‬
a.
b.
c.
d.
Molecular size,
Diffusibility,
Solubility,
Partition coefficient
❑ Compounds which can interact with drugs:
1.
2.
3.
4.
Methyl cellulose derivatives
Gum Tragacanth
High molecular weight polyethylene glycol
Non-ionic surfactant
❑ Examples for complexation reactions:
Physical adsorption
• Reversible
• Not affect the bioavailability.
Chemical adsorption
• Irreversible
• Affects the bioavailability.
❑ Examples of Adsorbents:
1- Charcoal
2- Bentonite
3- Vegum
4- MgO,
5- MgCO3
6- Mg trisilicate
7- Clays include Bentonite, vegum
Attapulgite
8- Attapulgite
❑ Examples for adsorption reactions:
A. PROMAZINE • If taken alone, there is a maximum bioavailability about 100%
• If taken with attapulgite, the bioavailability decreased to 80%
• If taken with charcoal, the bioavailability become 50%
• If taken alone, bioavailability about 100%
B. LINCOMYCIN • If taken before attapulgite - pectin suspension, the bioavailability is 100%
• If taken with the mixture at the same time, the bioavailability is 20%
• If taken alone, there is a maximum bioavailability about 100%
• If taken before kaolin-pectin suspension, the bioavailability is 100%
C. DIGOXIN
• If taken with the mixture at the same time, the bioavailability is 40%
• If it taken alone, the bioavailability is 100%
D. Quinidine
sulfate ‫ • مهم جدا‬If taken with kaolin pectin suspension, bioavailability is 46%
5- Surface Active Agent
Types of S.A.A:
Anionic → not taken orally
Cationic → not taken orally
Non-ionic → taken orally
Effect of S.A.A on absorption:
Below Critical Micelle Conc.
➢ Increasing concentration of the surfactant is accompanied by
increasing of the absorption.
2. Above Critical micelle conc.
➢ Increasing the concentration of surfactant, absorption decreases
due to micellization which entraps the drug inside it.
❑ Role of Surface-active agent:
➢ Affect permeability of GI tract by causing disorganization of lipid in cell membrane causing:
1. Fluidity of lipid in the biological membrane.
2. Increase flexibility.
3. Decrease interfacial tension.
4. Allow the passage of water-soluble drugs.
❑ Effect of surfactant on organic and inorganic materials:
1- Organic materials:
➢ Such as iodoform
➢ Surfactant decreases absorption of organic materials due to micellization.
2- Inorganic materials:
➢ Such as Potassium iodide
➢ Surfactant increases absorption of inorganic materials due to disorganization of membrane so increases
fluidity and absorption
❑
•
•
•
❑
1.
B. Distribution phase
• After absorption, drug distributed to body compartments such as (tissue and blood).
• Blood volume in adult (5.5 – 6) liters which flow one cycle per minute.
• Volume of plasma is about 3 liters.
• Blood flow is different from part to part.
❑ Types of organs according to blood flow:
A. Highly perfused organs:
➢ Have high blood supply so have rapid drug distribution
➢ as Kidney, liver, brain, Lungs and heart
B. Low perfused organs:
➢ Have low blood supply so slow drug distribution
➢ As Muscles and adipose tissue
C. Poorly perfused organs:
➢ very low blood flow or Nearly absence of blood flow
➢ as Skeleton
❑ Factors affecting distribution phase:
➢ Lipid solubility:
• lipid soluble drug will permeate through lipid membranes.
• Water soluble drugs with low molecular size diffuse through pores.
• Large molecules of low lipid solubility have special transport (active transport).
A- CELLULAR DISTRIBUTION
❑ Extracellular fluids:
➢ Examples:
•
Administration of phenobarbital (weak acidic drug) to 2 group of dogs, Dogs are subjected to drug in
acid and alkaline medium.
GROUP A
▪
▪
▪
Acidosis through inhalation of CO2 leading to ▪
acidification of blood.
Drug will be in unionized form
▪
absorption and distribution increased → low ▪
conc. in blood → high lipid solubility
GROUP B
Alkalosis through administration of NaHCo3
leading to alkalization of blood.
Drug will be in ionized form
absorption and distribution decreased → high
conc. in blood → low lipid solubility
B- DISTRIBUTION TO TUMER CELLS
•
•
•
There is limited vascular supply to tumor cell due to increased proliferation cells.
The drug cannot distribute to that area with effective conc. And to obtain effective conc.
We should increase the dose but this will increase side effects.
•
To solve this problem, Continuous IV dripping to get constant and continuous blood level should be used.
C- DISTRIBUTION TO CNS
•
•
Capillaries of brain differ in their permeability characters from other capillaries in body.
Because they have blood brain barrier (BBB) which is less permeable to water soluble substance.
❑ Examples:
Thiopental
Barbital
Dopamine
▪
▪
▪
▪
▪
▪
▪
▪
▪
▪
▪
High partition coefficient
High lipid solubility
Can pass BBB
Has short duration of action
Used in general anesthesia
Low partition coefficient
Low lipid solubility
Slowly penetrate BBB
eliminated from body before reach to effective conc
Used as sedative and hypnotic
Used in treatment of parkinsonism which caused by decrease dopamine conc. in
▪
▪
Penicillin &
tetracycline
▪
brain but dopamine is less effective as it is water soluble and can't pass BBB.
To solve this problem, use pro drug levodopa (inactive) form which can penetrate
BBB then metabolize in CNS and converted to dopamine (active)
Low lipid solubility so it is highly ionized and can't pass BBB so tetracycline can’t be
use in treatment of meningitis
Use sulfa drugs instead of tetracycline as prophylactic dose as sulfa is high lipid
soluble and can penetrate BBB.
D- PLACENTAL DISTRIBUTION
• Transfer of drugs from maternal blood to fetal blood by placenta
❑ Placental distribution affected by:
1. Lipid water solubility
2. Plasma protein binding
3. PH
4. Pka
❑ Examples of drugs that can transfer to fetus:
▪ Alcohol
▪ Nicotine
▪ Codeine
▪ Narcotics
▪ Barbiturates
▪ Analgesics
▪ Used as analgesics for pregnant women but found that it causes:
Thalidomide
a. 50 % of fetus dies
‫مهم جدا‬
b. 50 % of fetus with teratogenic effect.
Alcohol
May cause delayed response
Nicotine
Cause infant suffer from Abdominal cramps, pains, nausea and vomiting
Plasma Protein Binding
•
•
Major plasma proteins are albumin and globulin
Albumin is most generally bind with acidic drugs more than basic drugs while Globulin is bind with
corticosteroids
▪ More involved in the binding process - Acidic drugs are bound more than
Albumin
basic drugs because pH of the blood is slightly alkaline (pH 7.4)
Globulin
▪ Not widely involved in binding process - Corticosteroids bound to globulin
❑ Characters:
1. Increase half-life so increase duration of action and increase residence time so called store house.
2. Can't cross biological membrane.
3. Low glomerular filtration.
4. Act as physiological solubilizer as if drug is not bind by fixed percentage, it will ppt. → bishydroxy
coumarin (anti-coagulant) binds with 98 % so only 2% can give therapeutic effect.
5. Reduce absorption and distribution.
6. Displacement → one drug displaces another one from binding site due to its high affinity to protein so
increases free drug causing side effects.
❑ Conc of Mepacrine : ‫مهمـــــــــــــــة‬
➢ Plasma → 5000
Spleen → 9000
Liver → 21000
Elimination Phase
•
•
Distribution and absorption affect onset time but elimination affect duration of action.
Duration of action is related to:
a. frequency of administration.
b. The dose administered each time
• Drug with high T1/2 → have low frequency of administration
• Drug with low T1/2 → have high frequency of administration
❑ Elimination of drugs occurs through: ‫امتحان‬
Major eliminating organs
•
•
Renal “through kidney”
Biotransformation “through liver
metabolism).
Minor eliminating organs
•
•
•
•
Saliva excretion
Skin excretion
Biliary excretion
Pulmonary
A.RENAL EXCRETION
• Removal of unchanged drug from the body through kidney
❑ Characters of drugs eliminated by renal execration:
creatine phosphate in muscle
• If half-life increases this indicates kidney dysfunction.
• Rate of production of creatinine equal to rate of Characters of substances that used as exogenous
elimination
diagnostic agents:
• Normal individual conc. in blood (1 – 2 mg/100
1. Filterable and Non-toxic
ml)
2. Unbound to plasma protein
• If conc. of creatinine increases, this indicates
3. Easily analyzed
kidney dysfunction
4. Remain chemically uncharged
a. Water soluble
b. Low molecular weight
c. Slowly bio transformed
❑ Mechanisms of Renal Elimination:
1. Glomerular filtration.
2. Active secretion.
3. Active and passive tubular reabsorption.
Molecules that can pass
Molecules that cannot pass
Glomerular • Liquid plasma.
• Blood
filtration • Dissolved solute with low Molecular weight. • Plasma proteins
•
•
Active
secretion
• Drug that binds with plasma proteins
Energetic process in which acidic and basic drugs are execrated.
Characters:
✓ Need energy.
✓ Site specificity.
✓ Transfer against conc. Gradient.
B. BIOTRANSFORMATION
•
It is a process by which drug converted to another form that may be either active, less active or inactive.
❑ There is a difference between biotransformation and metabolism:
Metabolism
Biotransformation
✓ Process of biotransformation of food
staff
✓ Accompanied by producing energy
❑ Examples: ‫مهمة جدا جدا‬
Drug
Upon Biotransformation
Methanol (non-toxic)
Phenyl butazone (active)
Phenacetine (Active)
Codeine (Active)
Prednesol (Active)
Diazepam (Active)
Formaldehyde (toxic)
Oxyphene butazone (more active)
Paracetamol (more active)
Morphine (more active)
Prednisolone (more active)
Nor diazepam (more active)
Active Reabsorption
•
Reabsorption
Include reabsorption of all essential substances
• Glucose, vitamins, water, Na, K
Passive reabsorption
Depend on PH partition theory
For acidic drugs
For basic drugs
Make alkalization of urine by NaHCO3 so Make acidification of urine by NH4Cl so basic drugs
acidic drugs will be ionized (low lipid will be ionized (low lipid solubility) so increase
solubility) so increase secretion.
secretion
❑ Notes:
•
•
•
•
•
•
Daily Rate of blood flow to kidney is 1700 L/ day
Half of this amount is plasma (850 L / day)
Only 20 % filtered by glomerular filtration (170 L /day)
This means that execration per hour is 7 – 8 L/hr
This means that execration per minute is 130 ml/min ‫مهم جدا‬
but they found that only 60 ml / hr are execrated in urine and the rest of the quantity is reabsorbed by
reabsorption
❑ Renal Clearance:
❑ Why does biotransformation mostly cause deactivation of drugs?
As it converts drugs to more water-soluble compound (less lipid soluble) which can easily clean by kidney
❑ Two phases of biotransformation:
Phase I
Phase II
✓ Include addition of functionally reactive group ✓ Include conjugation of reactive group with
by oxidation, reduction, hydrolysis or other
conjugating agent such as glycine – glutathione
methods.
–glucuronic acid
✓ If drug have a functional group, it will pass
directly through phase II without undergoing
phase I
❑ Examples of Phase I:
Reaction
S-oxidation
Aromatic hydroxylation
Aliphatic hydroxylation
Oxidative – o – de alkylation
Azo reduction
Hydrolysis
Acetylation
• The operative mechanism of renal excretion.
urinary excretion rate
U×V
• Renal clearance (R.C) = drug plasma conc = Cp
• U→ amount of unchanged drug in urine.
• V→ Volume of drug excreted per minute.
• Cp → plasma conc of drug
❑ Clearance ratio:
Example
✓
✓
✓
✓
✓
✓
✓
Chlorpromazine → chlorpromazine sulfoxide
Phenyl butazone → Oxyphene butazone
Meprobamate → hydroxyl meprobamate
Phenacetine → paracetamol.
Prontosil → sulfanilamide
Acetyl salicylic acid → salicylic acid
Sulfa drugs → N – 4 – acetyl sulfanilamide
❑ Problem and solution:
• Relation between renal clearance of drug and glomerular.
Renal Clearance
R.C
• Clearance ratio= glomerular filtration rate = G.F (130 ml/min)
•
• If the clearance ratio = 1 (R.C=G.F)→ the drug is completely excreted by glomerular filtration
• If the clearance ratio <1 (R.C<G.F) → So drug is reabsorbed again
• If the clearance ratio >1 (R.C>G.F)→ So drug execrated by GF and active secretion
❑ Kidney function test:
➢ Can be done by 2 methods:
Endogenous substance
✓ Process by which drug converted by another form.
✓ Accompanied by formation of more active, less active
or inactive form of drug
Exogenous substance
• Substance which secreted in body as creatinine. • Substance which injected IV as inulene.
• Creatinine is the metabolite of creatine and • Rapidly execrated from the body half-life is 6 min
•
Problem → Sulfa drugs lead to formation of renal calculi as acetylated sulfa drugs is less water soluble so
present in high conc. in blood and exceed saturation conc. so ppt forming calculi
Solution → By using an additive combination of 4 – 5 types of sulfa drugs so conc. of sulfa drugs decreases
and ability to ppt decrease and can't reach saturation conc
❑ Examples of phase II:
Reaction
Benzoic acid (less water sol.) + glycine
Chloramphenicol + glucuronic acid by
glucouronyl transferees
Salicylamide + sulfate
❑ Factors affecting biotransformation:
Product
Hippuric acid (water sol.)
Chloramphenicol glucuronide
Salicylamide sulfate
Different species (rats-cats-human) have different metabolizing enzyme so show different
biotransformation.
• Chlorpromazine is bio transformed by different mechanisms ‫مهم جدا‬:
a. Hydroxylation.
b. Sulfoxidation.
c. N-oxidation.
d. N-de methylation.
• Rate of biotransformation in human slower than animal so human show slow inactivation & animal
show rapid inactivation. (Half-life In animal < Half-life in human).
• Metabolizing enzyme varies with time.
In geriatrics
In fetus
• Limited renal function.
• Have low hepatic enzymes.
• Decreasing liver microsomal enzyme.
• Have low metabolizing enzymes such as
glucouronyl transferase enzyme.
• Decrease Function of liver & kidney so should ↓
dose to avoid agglomeration.
• No conjugation so leads to accumulate
substances so dose should be decreased
• Low rate of biotransformation.
• Limited renal excretion
❑ Hepatitis:
✓ Hepatic enzyme decreased so biotransformation decreased & ↑ t1/2 so may cause accumulation
❑ Acetylation of PAPA:
✓ Biotransformation increase in diabetic patient as it may cause high biotransformation so low
half-life
✓ Biotransformation decrease in hyperthyroidism patient as it may cause low biotransformation so
high half-life.
• Variation between individuals.
• An average dose may under medicate group of patient and cause toxicity in another group.
• Resistant individuals, need more dose than normal dose to give same effect.
• Sensitive individuals need low dose than normal dose to give same effect.
❑ Examples:
Di phenyl hydantoin
Average plasma level of same dose is (2.5 – 40 ug/ml) so 16-fold difference.
Bis hydroxyl coumarin
Used as anti-coagulant with 14-fold variation in blood level
• Variation based on genetic difference
❑ Isoniazid:
When some dose of drug is administered to Caucasians, it shows that:
✓ 50 % rapid in activator and have short half-life so high biotransformation.
✓ 50 % slow in activator and have long half-life so low biotransformation.
✓ So, they need different doses from the same drug.
✓ Drug may change metabolism due to inhibition or stimulation of hepatic enzymes
Hepatic Enzyme Induction
Hepatic Enzyme Inhibition
✓ One drug increase rate of biotransformation of
✓ They decrease metabolism and increase halfthe other drug when taken together so high
life
metabolism and low half-life.
Examples:
Examples:
• Alcohols  metabolism of phenobarbital and • Warfarin metabolism of tolbutamide.
tolbutamide.
• Chloramphenicol  metabolism of hexobarbital.
• Phenyl
butazone

metabolism
of • Isoniazid metabolism of phenytoin.
aminopyridine.
• Methandrostolone  metabolism of oxyphenyl
• Barbiturates  metabolism of digoxin, bilirubin
butazone.
& bis hydroxycoumarin.
• Chloral hydrate  metabolism of bis hydroxyl
coumarin.
Effect of drug
Pharmacogenetics
Inter subject
variation
Pathological
conditions
Age
Species difference
•
❑ Notes:
• Bilirubin found in plasma in conjugated form.
• When present in unconjugated form (free form) tis increase bilirubin and cause hyper bilirubinemia causing
jaundice.
• To solve this problem, give phenobarbital which stimulate biotransformation of decomposition of bilirubin
and increase conjugation of free bilirubin but it is unsuitable in case of infants as barbiturates or
phenobarbital have a great sedative effect which may be harmful for baby.
• Using phototherapy as bilirubin is photo-sensitive.
C. BILIARY EXCRETION
✓ Liver excrete (0.5 – 1) L/day of bile into the duodenum through bile duct but 90% of excreted bile is actively
reabsorbed
✓ As it is highly ionized with low lipid solubility and move against conc. gradient so can't be absorbed by passive
diffusion and it is actively reabsorbed.
✓ After meals, gall bladder is contract and this increase delivery of biliary excretion.
❑ Composition of Bile:
➢ Cholic acid, Deoxy cholic acid & other sodium salts.
❑ Entero-Hepatic Circulation:
✓ Many drugs excreted by liver cells into the bile by active process for acidic and basic drugs.
✓ Most are reabsorbed from intestine then secreted again from liver until complete excretion.
❑ Examples of biliary excretion:
• Ovulation inducing agent.
Clomiphene
• Completely excreted through biliary excretion by any route of administration
Quaternary
• Completely ionized and not reabsorbed
ammonium
• Excreted through biliary excretion
compounds
Rifamycin &
• (50% - 100%) of dose excreted in bile
stilbsterol
❑ Storage in gall bladder:
• Drugs may store in gall bladder then release to small intestine.
Why the second peaks appear?
• Co inside with food intake due to storage of drug in gall bladder
and after meal, contraction of gall bladder release bile salt.
• Ex. Diazepam – digitalis.
❑ Physical factors affecting biliary excretion:
• Fat soluble substances of high M.wt expected to excrete through bile rather than in urine.
• Minimum M.wt required for biliary excretion of cations differs from anion which
demonstrates different mechanism.
Molecular
weight
• Drugs with M.wt 500 will excrete in bile.
• Drugs with M.wt (300 – 400) excreted in both urine and bile.
• Drugs with M.wt less than 300 excreted in the urine
Polarity
• Strongly polar groups fond to be responsible for biliary excretion
Structural factors of no. of sulfonamides in the rats demonstrated their effect by one of
the following factors:
Molecular
a. Changing lipid solubility.
Structure
b. Shape of molecules.
c. Intramolecular relationship of polar or non-polar part of molecule.
D. SALIVARY EXCRETION
• Depend on PH partition theory.
• Saliva acts as lipoid membrane allow passage lipid soluble substances only.
• Allow lipid soluble compounds to move from plasma to saliva.
• PH of saliva (5.5 – 8.5).
❑ Excretion in saliva may be:
• Active: if conc. of drug in saliva > conc. in blood so transfer against conc. ingredient from low conc. (blood)
to high conc. (saliva) by active secretion.
• Passive: if conc. of drug in blood < conc. in saliva so transfer with conc. ingredient from high conc. (blood) to
low conc. (saliva) by passive excretion.
✓ Actively secreted in saliva.
Lithium
✓ Its conc. in saliva 2- 3 times more than in blood
Penicillin
✓ Actively secreted in saliva.
&
✓ There is a competition between them for excretion through saliva so long
Probenecid
half-life of penicillin
❑ Examples of drug excreted in saliva:
1) Sulfonamides
2) Phenobarbital
3) Phenytoin
4)
5)
6)
7)
Salicylates
Theophylline
Quinidine
Digoxin
❑ Side effects:
➢ Excretion through saliva may cause localized side effects such as:
a. Certain antibiotics excretion of certain antibiotics from blood to saliva gives black hairy tongue
b. Phenytoin Excretion through saliva cause gingival hyperplasia.
E. MAMARY EXCRETION
✓ Excretion through breast milk.
✓ Depend on PH partition theory.
✓ PH of breast milk (6.8 – 7.3).
✓ In normal conditions:
▪ Conc. of weakly acidic drugs in milk is lower than in blood.
▪ Conc. of weakly basic drugs in milk is equal or more than in blood.
✓ Ethanol and tetracycline have low molecular weight so it diffuses through membranes pores so conc. at
plasma and milk may equal
F. SKIN EXCRETION
✓ Drugs excreted through skin into sweat
✓ PH of skin (5 – 5.5) acidic act as a protective mechanism so prevent growth of M.O.
✓ Concerned mainly with acidic drugs.
✓ We can identify if the substance excreted from skin by taking a skin swap.
Examples of drugs excreted through skin:
• Br2 – I2 - Salicylic acid – benzoic acid.
• Alcohols – iron – lead.
• Anti-purine.
G. GIT EXCRETION
• Basic drugs can be excreted to GIT after IV administration
• Ex. Nicotine – quinine
• In stomach: highly ionized, low lipid soluble, so not reabsorbed and excreted.
• In intestine: highly unionized so reabsorbed
H. PULMONARY EXCRETION
• Volatile & gases excreted through lung.
• Drug released through expired air.
Examples:
• Ether: used in general anesthesia.
• Paraldehyde: used as sleep inducing agent.
Breath test for drinking drivers:
• Breath is received on sheet of paper (TLC) treated with material sensitive to alcohol.
• If breath contains alcohol, color of sheet will change.
Bioavailability Studying
❑ Drugs not required in vivo bioavailability:‫امتحاااااان اقسم باهلل‬
1- Intravenous solutions → as there is no absorption phase
2- Topically applied drugs but transdermal drugs require in vivo bioavailability ‫مهم جدااااااااااا‬
3- Substances not intended to be absorbed as antacids, antidiarrheal and diagnostic drugs such as radio-opaque
media.
4- Drugs administered by inhalation as asthmatic attack drugs
5- Oral solutions as elixirs, syrup and tincture ‫مهم جدااااا‬
❑ Oral dosage forms:
Advantages
1. Patient acceptability.
2. Large surface area in small intestine which
Disadvantages
1- Variabilities affecting absorption:
• pH → stomach is acidic while intestine is
cause high absorption.
3. Rich of blood supply so increase absorption.
4. Can be formulated as Sustained release
formulation as it is simply increase absorption
so we may decrease the dose.
5. Zero order-controlled release which prevents
formulation of peaks & troughs so reduce the
dose frequency and avoid fluctuations.
6. Commercial cost in comparison to parenterals.
23456-
alkaline.
• Presence of food
• Difference in Gastric emptying rate
• Body posture.
• Drug interaction.
• Pathologic conditions.
• Gender variance (Male and Female)
• Race difference
• Disease state
Adverse reactions as irritant drugs that can damage
mucosa
First pass effect and metabolic activity
Enzymatic reactions and secretions of GIT
Effect of extreme acidic pH → acid labile drugs
degraded by acidity of stomach.
Difference in intestinal motility (hyper and hypo
motility)
❑ Factors affecting drug Half-Life:
1- Age:
➢ In elderly people, decrease liver function so increase half-life of drug
➢ In infants, Enzyme system not completed so increase half-life
2- Species difference:
➢ Biotransformation is: Slow in human and rapid in animals so this increase half-life in human and
decrease half-life in animals.
3- Physiological properties:
➢ Change in PH which may cause changing in plasma protein binding.
4- Pathological properties:
➢ Kidney and liver disease affect execration and half-life
5- Tissue localization:
➢ Affinity of drug to be in tissue
6- Protein binding
❑ Factors affecting dosing of drugs to elderly:
1.
2.
3.
4.
5.
6.
7.
Physiologic condition.
Increasing of fatty tissue and decreasing of metabolic process.
Fat soluble drugs may alter Vd.
Free drug increased due to reduced drug protein binding.
Perfusion of drug to GIT region decreased and drug absorption affected.
Sensitivity of liver and kidney.
Receptor Sensitivity or response to drug may be modified
Experimental methods to study GIT absorption
A. In Vitro (Everted Sacs)
❑ Advantages:
• Not consumed many animals
• Simple for screening
• Distinguish between active and passive absorption.
❑ Disadvantages:
• Non-physiologic as no blood vessels.
• Permeability may be changed outside the body.
❑ Steps:
▪
1.
2.
3.
4.
5.
A rat is anesthetized with pentobarbal.
A midline abdominal incision is made.
The small intestine with a length of 10- 15 cm is rapidly removed and everted with a glass rod.
The sac is securely ligated at both ends and filled with bicarbonate buffer solution.
The sac is incubated at 37°C in a glass vessel containing the same buffer solution and gassed with 95%
O2 /5% CO2
6. After 5 min, the drug solution is added to the glass vessel and the preparation is further incubated.
7. After given time intervals, the fluid from the everted sac is removed and the volume determined.
8. The concentration of the drug transported from the mucosal to the serosal side is determined by appropriate
analytical methods.
Used to compare between the 2 results and determine if the 2 drugs are significant and bioequivalent
or not
Important practical problem
Following I.V administration of a dose of 1.5 mg of digoxin dissolved in diluted alcohol to a patient with congestive
heart failure.
The following urinary excretion data were obtained:
Time (day)
0-1
1-2
2-3
3-5
B. In Situ
a) Perfusion technique.
b) Loop technique.
‫انظر للشرح العربى فى المحاضرة‬
C. In Vitro
❑ Criteria for in vivo bioavailability tests:
•
It should be designed to reduce as many possible sources of variation.
Urine Conc. (µg/ml)
0.01386
0.00815
0.0050
0.0033
Determine
a. T1/2 graphically
b. Overall elimination rate constant (KE)
c. Urinary excretion rate constant (Ke)
d. biotransformation excretion rate constant (Kb)
e. Percentage of Ke & Kb
f. T1/2 in patient suffering from anuria
g. T1/2 in patient with 40% reduction in biotransformation
❑ Factors that reduce variation:
A. Subject to subject variation (intersubject variation( :
▪ Normal healthy volunteers
▪ Age should be 20 – 50 years
▪ Body weight between 55 – 90 Kg
▪ Experimental must be done on healthy volunteers.
▪ Numbers of males and females must indicate.
▪ Normal body fluid (urine – blood sample)
B. Cross over study:
▪ Individuals or volunteers divided into 2 groups then Group A take drug A and group B take drug B.
▪ Wait wash out period to be sure that complete elimination of drugs from body
▪ Then each group receive dose of other group (Group A take drug B and Group B take drug A
❖ Wash out period ‫امتحان‬:
▪ It is the time which allowed all dose to be execrated from body
▪ At least 10 times of half-lives of drugs.
C. Bioavailability study conditions:
➢ Condition must be identical before and after administration of tested drug for the 2 groups of volunteers:
a. Time before studying.
b. Period of fasting before and after administration.
c. Type of food & drink must be controlled.
d. Degree of physical activity must be identical as physical activity increase absorption and
bioavailability
D. Frequency and duration of taking blood samples:
▪ We must take at least 3 points for each phase to draw bioavailability curve.
▪ Blood level curve must define absorption and elimination phase.
▪ Blood samples should be continued until (87 – 95 %) of drug eliminated or until
▪ plasma drug level decreased to (5 – 10 %) of peak conc
E. Assay procedures:
▪ Blood sample should be stored and treated under the same condition.
▪ It is better to assay drug by 2 different methods such as:
✓ HPLC.
✓ Spectrophotometry.
✓ Radio-immunoassay
F. Statistical analysis of blood level:
Urine volume (ml)
1000
1200
1400
2520
urinary excretion rate after midpoint =
Urine volume × urine conc
time interval
100
Mid-point
Urinary exec. Rate after
mid-point
(1000 × 0.01386)/1 = 13.86
(1000 ×0.00815)/1= 9.78
(1000 ×0.0050)/1= 7
(1000 ×0.0033)/2= 4.2
(0+1)/2 =0.5
(1+2)/2 =1.5
(2+3)/2 = 2.5
(3+5)/2 =4
10
1
0
1
2
3
4
5
a. Half-life = 2.1 day
b. K E =
c. K e =
0.693
T1/2
=
0.693
2.1
Y−intercept
dose
= 0.341 𝑑𝑎𝑦 −1
16
= 1500 = 0.011 day −1
‫مهم‬
d. KE=Ke + Kb → Kb= KE-Ke = 0.341 – 0.011 = 0.33 day −1
ke
0.011
e. % Ke = K × 100 = 0.341 × 100 = 3.2 %
E
Kb
0.33
f. % K b = K × 100 = 0.341 × 100 = 96.8 %
E
g. In case of anuria→ no urine → Ke= zero
KE=Ke + Kb = 0 + 0.33 = 0.33 day −1
T1/2 =
0.693
KE
=
0.693
0.33
= 2.1 day
h. Kb (remain) = 60% So,
KE = Ke + Kb
KE = Ke + (0.6× Kb) = 0.011 + (0.6× 0.33) → KE = 0.209 day −1
T 1/2 = 0.693 / 0.209 = 3.31 day
❑ Modification to increase bioavailability:
A. Mucoadhesive drug delivery:
• Hydrophilic polymer that interact with mucosal membrane forming H-bond with mucosal
membrane.
• It enhances absorption by prolonging the residence time, increase local conc. in the absorption
region and protect drug from degradation by gastrointestinal fluids.
Solutions
Suspensions
A. Social drugs:
• Coffee and Tea stimulate the acid production in the stomach so gastric emptying initially increases then
followed by reduction as Ergotamine and nitrofurantoin by increasing rate and extent of absorption.
• Caffeine increases Plasma concentration of epinephrine and norepinephrine and increases blood flow.
• Tobacco and nicotine stimulate salivation and decrease blood flow to mucosa
• Caffeine:
• Ethanol decrease gastric emptying rate and increase acid secretion and blood flow so increase
bioavailability of chloralhydrate and chlordiazepoxide, meprobamate.
B. Body posture:
Effect of superior position (lying on back):
• Decreases rate and extent of absorption on sodium salicylate.
• Decreases rate of absorption of aspirin without affecting extent of absorption.
Determination of bioavailability of drugs
1) Direct method:
2) Indirect method:
• Blood data
• Acute pharmacologic effect
• Urine data
• Clinical response
A. Acute pharmacologic effect:
• Used in case of quantitative measure is not available or there is no sufficient accuracy in analysis or
drug may be potent.
• We determine the AUC after 3 half-lives of drugs
• Examples:
✓ Heart rate
✓ Blood pressure
✓ Pupil diameter
B. Clinical response:
• Used if drug is:
1. Unavailable, this cause lack of response.
2. Reasonally available, cause good response.
3. Highly available, cause toxicity.
• Disadvantages:
• Require high number of volunteers.
• Inter subject variation is high.
Dosage form factors affecting GIT absorption
• May affect bioavailability due to forming of poorly soluble non-absorbable complex
Excipients Examples:
✓ Phenobarbital + PEG.
✓ Tetracycline + Ca+2
• May affect bioavailability
Phenytoin (antiepileptic drug):
Diluent
✓ Calcium sulfate dehydrate diluent, decrease absorption of phenytoin.
✓ Calcium sulfate dehydrate changed to lactose which is highly soluble in water so cause
overdose of drug leading to toxicity
• Affect biological membrane so affect permeability and affect absorption
Surfactant
• If present in form of monomer, it causes disruption to the intermolecular structure of lipid and
Soft gelatin capsule
❑ Other factors affecting bioavailability:
cause changing of permeability and decrease integrity.
• Increasing conc. Above CMC will decrease bioavailability and absorption.
• If increase viscosity, GER decreased, GIT motility decreased, dissolution rate decreased and
diffusion of drug decreased so affect absorption of drug.
• Increasing viscosity may increase absorption in case of acidic drugs because of decreasing
GER may permit the long contact of these drugs with the stomach leading to increasing
Viscosity
absorption any bioavailability
Examples:
✓ Phenobarbital sodium + sucrose, increase viscosity so cause decrease of absorption
✓ Na salicylate +methyl cellulose, increase viscosity so cause decrease of absorption
✓ Na salicylate + gum solution, increase viscosity so cause decrease of absorption
The Influence of the Dosage Form on the Bioavailability of Drugs
• The absorption of drugs from solution dosage forms (syrups) is a fast & complete process, where the
drug will be available in a soluble form ready for direct absorption, it doesn’t need to be broken or
disintegrated first, because it is already available in a direct liquid form
• bioavailability of solution may be affected by:
✓ Chemical stability of drug in solution.
✓ Occurrence of a Complexation reaction.
✓ Solubilization or micellization
✓ Viscosity of solution
• Bioavailability of suspensions may be affected by:
✓ Particle size of drug as the reduction of the drug particle size will increase the effective surface
area & enhance the dissolution rate & the absorption rate of the drug.
✓ Crystal form (amorphous or crystalline)
✓ Complexation between excipients.
✓ Inclusion of surfactant, surfactants are added as wetting agents to suspensions to enhance the
wettability of hydrophobic drugs and may give a deflocculated or flocculated suspension
• These are soft or elastic gelatin shells encapsulating a drug which is dissolved, dispersed or suspended
in a non-aqueous vehicle or solvent, because aqueous solvent will dissolve gelatin shell
• Bioavailability of soft gelatin capsules may be affected by:
✓ The solubility of the drug in the vehicle which will control the release of that drug from that
vehicle.
✓ The particle size of the drug if formulated as a suspension in the vehicle
✓ The addition of wetting agents to the formulation.
✓ Complexation reaction.
✓ Crystal form
• Bioavailability of tablets may be affected by:
a. All physio-chemical properties of the drug
b. Diluents
c. Binders
d. Disintegrants
e. Lubricants
f. Compression or compaction pressure applied
g. Method of tablet manufacturing employed
h. Storage
Tablet and coated
tablet
B. Lipidization strategies:
• Oral absorption of peptides and proteins (hydrophilic) increased 140 times by addition of palmitic
acid with protease inhibitor
C. Natural transport system:
• Competition such as uracil and 5-fluorouracil.
• L – Methyl dopa is actively absorbed 7 times more than passively absorption.
• Formation of L-valyl ester pro-drug of acyclovir increase absorption
D. Co-administration of drugs which help in increasing absorption:
• Surfactants, Bile salts & chelating agents
‫دُمتم ساملني‬