EXCRETION OF DRUG
Dr. Muslim Suardi, MSi., Apt.
Faculty of Pharmacy
University of Andalas
2009
Excretion of Drug
“Removal of the intact drug”
Metabolites
Drug molecules
Renal
Sweat
Bile
EXCRETION
Nail
Hair
Saliva
Other fluids
Milk
Excretion of Drug
RENAL
EXCRETION
RENAL EXCRETION
•
•
•
•
•
•
Nonvolatile drug
Polar (easily removal)
Water soluble
Low MW, <300
Metabolites
Slowly biotransformed by the liver
Feces
• Drug not absorbed by GIT
• Bile excretion, no absorption in intestinal
Biliary Excretion
Drug Excretion
Breast Milk
Affect on baby
Lung
• Important in excretion of general
anesthetic drug
• Non polar
• Gas
• Drug/metabolites in small amount
Tears
• Example: Rifampicin
• Important in drug information services to
patients
Saliva
• Example: Excretion of Potassium Iodide
Sweat
• Smelly
Kidney
• Main excretory organ for removal of
metabolite waste
• Plays major role in maintaining the normal
fluid & composition
• Maintain salt & water balance: kidneys
excretes electrolytes, water, waste product
• Located in the peritoneal cavity
• Nephrons: basic functional unit
Nephrons
•
•
•
•
Basic functional unit
Responsible for the removal of metabolite
Maintain of water & electrolyte balance
Reabsorb of water by longer loops of
Henle
Kidney blood supply
• Kidney is supplied by blood via the renal
artery
• Afferent arteriole carries blood toward a
single nephron into glomerular portion of
nephron (Bowman’s capsule)
• Filtration of blood occurs in the glomeruli
in Bowman’s capsule
Kidney blood supply
• From glomerulus, the blood flow out via
the efferent arterioles
• Then into a second capillary network that
surrounds the tubules
RENAL DRUG EXCRETION
Include any combination of:
• Glomerular filtration
• Active tubular secretion
• Tubular re-absorption
Glomerular Filtration
• About 180 L of fluid/day are filtered
through the kidneys
• Average urine volume is 1-1.5 L
• Besides fluid regulation, the kidney also
regulates the retention or excretion of
various solutes & electrolytes
Glomerular Filtration
• Most small molecules are filtered through
glomerulus from plasma
• The filtrate contains some ions, glucose, &
essential nutrients as well as waste
products
Glomerular Filtration
• Waste products such as urea, phosphate,
sulfate, & other substances
• The essential nutrients & water are
reabsorbed at various sites including the
proximal tubule, loops of Henle, & distal
tubules
Glomerular Filtration
• Both active reabsorption & secretion are
involved
• The urine volume is reduced
• Urine generally contains a high
concentration of metabolic wastes &
elimination drug products
Glomerular filtration
•
•
•
•
Unidirectional process for most small MW
Including: Non-ionized & ionized drugs
Protein bound drugs (large), not filtered
Pore diameter of glomeruli capillary: 70
nm
• Hydrostatic pressure
Renal Function
“An indication of the state of the kidney &
its role in physiology”
Creatinine, urea, electrolytes, & inulin were
used to determine renal function.
These measures are adequate to determine
whether a patient is suffering from kidney
disease.
GFR
• To know renal patients
• GFR is measured by using a substance
that is eliminated by filtration only
• The substance is neither reabsorbed nor
secreted
Glomerular Filtration Rate
• Inulin & Creatinine
• Clearance of inulin will be equal to the
GFR (125-130mL/min)
Calculation of GFR
• By comparing urine creatinine levels with
the blood test results.
• It gives a more precise indication of the
state of the kidneys.
Inulin
•
•
•
•
•
Polyvalent carbohydrate
No protein binding
No secretion into tubule
No reabsorption from tubule
Excretion into urine merely by glomeruli
filtration
• Plasma inulin is excreted by filtration only
& no reabsorption
Glomerular filtration
• The value for the GFR correlates fairly well
with BSA
• GF of drugs is directly related to the free
drug concentration in plasma
• As the free drug concentration in plasma
increases, the GF for the drug will
increase proportionally
GFR
• The GFR is expressed in mL/min.
• For most patients, a GFR over 60 mL/min
is adequate.
• GFR measurements can aid a
nephrologist in deciding when to initiate
dialysis or renal transplantation.
Corrected GFR
• Very often, the GFR is expressed as
ml/min/1.73 m2.
• GFR needs to be corrected for the BSA
• Most adults have a BSA that approaches
1.7 (1.6-1.9), extremely obese or slim
patients should have their GFR corrected
for their actual BSA.
• BSA can be calculated on the basis of
weight & height.
Ampicillin
•
•
•
•
Excretion mainly via glomeruli filtration
Therapeutic ratio: very wide
May be excreted via bile
GFR decrease, non renal excretion
increase
• No individualization in dosage regiment
Furosemide
• GFR decrease, non renal excretion
increase
• No individualization in dosage regiment
Kanamycin
• Excretion primarily by renal clearance
• Narrow therapeutics index
If Cl < 35 mL/min:
• 1. Dose should be reduced
• 2. Usage should be considered
NOMOGRAM
• Relationship between GFR & Dose
• Avoid over dose
• Calculation the proper dosage regimen
A quick dosage regimen adjustments for
patient with characteristics requiring
adjustments such as:
Age
BW
Physiology state
NOMOGRAM
• Some nomograms make use of certain
physiologic parameters, such as serum
creatinine concentration, to help modify
the dosage regimen according to renal
function
• For marketed drugs, the manufacturer
often provides tabulated general guidelines for use in establishing a dosage
regimen for patient, including L & M dose
NOMOGRAM
• The result displayed diagrammatically on
special scaled axes to produce a simple
dose recommendation based on patient
information
Active Renal Secretion
• A carrier-mediated system that requires
energy input, because the drug is
transported against a concentration
gradient
• Carrier system is capacity limited & may
be saturated
• Drugs with similar structures may compete
for the same carrier system
Active Renal Secretion
• 2 active renal secretion systems: weak
acids & weak bases
• Ex: probenecid will compete with penicillin
for the same carrier system (weak acid)
• Active tubular secretion rate is dependent
on renal plasma flow
• Compound commonly used to measure
active tubular secretion: PAH, Diodrast
Active Renal Secretion
• Both of substances are filtered by the
glomeruli & secreted by the tubular cells
• Active secretion is extremely rapid
• All the drug carried to the kidney is
eliminated in a single pass.
• The clearance of these compounds,
reflects the effective renal plasma flow
(ERPF)
• 425-650 mL/min
Active Renal Secretion
• Drug that is excreted solely by glomerular
filtration, t1/2el may changed markedly in
accordance with the binding affinity of the
drug for plasma protein
• In contrast, protein binding has very little
effect on t1/2el of a drug excreted mostly
by active secretion
Active Renal Secretion
• Because drug protein binding is reversible,
the bound drug & free drug are excreted
by active secretion during the first pass
through the kidney.
• Ex: Some of the penicillin are extensively
protein bound, but their elimination half
lives are short due to rapid elimination by
active secretion.
Tubular Reabsorption
• Occurs after the drug is filtered through
the glomerulus
• Can be active or passive
• If a drug is completely reabsorbed (eg.
glucose), then the value for the clearance
of the drug is approximately zero
• For drugs that are partially reabsorbed,
clearance value will be < GFR of 125-130
mL/min
Tubular Reabsorption
• Reabsorption of drugs that are acids or
weak bases is influenced by the pH of the
fluid in the renal tubule (ie. urine pH) &
pKa of the drug.
• Both of these factors together determine
the % of ionized & unionized drug
• Generally, unionized species is more lipid
soluble & has greater membrane
permeability
Tubular Reabsorption
• The unionized drug is easily reabsorbed
from the renal tubule back into the body
• This process of drug reabsorption can
significantly reduce the amount of drug
excreted, depending on the pH of the
urinary fluid & pKa of the drug
• The pKa of the drug is constant, but the
normal urinary may vary from 4.5 to 8.0
Tubular Reabsorption
• Variation of urinary pH depending on:
1. Diet
2. Pathophysiology
3. Drug intake
Higher urine pH caused by:
• Vegetable diets
Lower urinary pH caused by:
• Diets rich in carbohydrates
• Diets rich in protein
Drug
• Ascorbic acid & NH4Cl may decrease the
urine pH
• Antacid (Na2CO3) may increase the
urinary pH
• I.V fluids, such as solutions of HCO3- or
NH4Cl, are used in acid-base therapy.
• Excretion of these solution may drastically
change urinary pH & alter drug
reabsorption & drug excretion
Tubular Reabsorption
• % of ionized weak acid drug
corresponding to a given pH can be
obtained from the Henderson-Hasselbalch
equation
Tubular Reabsorption
Henderson-Hesselbalch Equation
For weak acids
[ ionized drug ]
pH = pKa + log ______________
[ unionized drug ]
Tubular Reabsorption
• The extent of ionization is more greatly
affected by changes in urinary pH with a
pKa of 5 than with a pKa of 3
• Weak acids with pKa values < 2 are highly
ionized at all urinary pH values & are only
slightly affected by pH variation
Tubular Reabsorption
Henderson-Hesselbalch Equation
for weak base
[ unionized drug ]
pH = pKa + log ______________
[ ionized drug ]
Tubular Re-absorption
• The greatest effect of urinary pH on reabsorption occurs with weak base drugs
with pKa values of 7.5 - 10.5
Tubular Re-absorption
• From the Henderson-Hesselbalch
relationship, a concentration ratio for the
distribution of a weak acid or basic drug
between urine & plasma may be derived
Tubular Re-absorption
Urine-plasma ratio for weak acids:
(pH urine – pKa)
1+ 10
U/P = ------------------------1 + 10 (pH plasma – pKa)
Tubular Reabsorption
Urine-plasma ratio for weak bases:
(pKa - pH urine)
1+ 10
U/P = ------------------------(pKa
pH
plasma)
1 + 10
Amphetamine
• Weak base
• Will be reabsorbed if the urine pH is made
alkaline & more lipid-soluble non-ionized
species are formed
Amphetamine
• In contrast, acidification of the urine will
cause the amphetamine to become more
ionized (form a salt)
• The salt form is more water soluble & less
likely to be reabsorbed & has tendency to
be excreted into the urine more quickly
Salicylic acid
• Weak acid
• Alkalination of the urine causes more rapid
excretion of the drug
Clinics
• Weak base drug will be excreted or will not
be absorbed in big amount in acidic urine
• Weak acid drug will be excreted rapidly in
alkaline urine
• In clinics: important in barbiturate toxicity
treatment. Barbiturate a weak acid with
pKa of 7.2
• The ratio of ionized form may be change
by urine pH modification
DRUG CLEARANCE
• A pharmacokinetic term for describing
drug elimination from the body without
identifying the mechanism of the process
• “Vol of fluid clear of drug per time unit”
DRUG CLEARANCE
• The fixed vol of fluid (containing the drug)
cleared of the drug per unit of time
• The units of clearance are vol/time
(mL/min, L/hr)
• Ex: if Cl‫ ז‬of penicillin is 15 mL/min in a
patient & penicillin has a Vd of 12 L, then
from the definition, 15 mL of the 12 L
would be cleared of drug per min
DRUG CLEARANCE
• Alternatively, Cl‫ ז‬may be defined as the
rate of drug elimination divided by the
plasma drug concentration
• The volume of plasma eliminated of drug
per unit time
• Practical way to calculate clearance based
on plasma drug concentration data
BILLIARY
EXCRETION
BILLIARY EXCRETION
• An important system for the secretion of
bile & excretion of drugs
• The common bile duct empties into the
duodenum
• Bile primarily consists of water, bile salts,
bile pigments, electrolytes, & to a lesser
extent, cholesterol & fatty acids
BILLIARY EXCRETION
• Molecular weight & excretion
• > 500 mainly excreted in the bile
• 300-500, excreted both in urine & bile. For
these drugs, a decrease in one excretory
route results in a compensatory increase
in excretion via other route
• < 300, almost exclusively excreted via
kidney
BILLIARY EXCRETION
• Drugs excreted into bile are metabolites,
very often glucuronide conjugates
• Formation of a glucuronide increases the
MW by the nearly 200, as well as
increasing the polarity
• Excreted into bile: digitalis glycosides, bile
salts, cholesterol, steroids, indomethacin
BILLIARY EXCRETION
• Compounds that enhance bile production
stimulate billiary excretion of drugs
normally eliminated by this route
• Phenobarbital: may stimulate the billiary
excretion of drug
• In contrast, compounds that decrease bile
flow or pathophysiologic conditions that
cause cholestasis will decrease billiary
drug excretion
BILLIARY EXCRETION
• The route of administration may also
influence the amount of the drug excreted
into bile
• Drugs given orally may be excreted by the
liver into the bile to a greater extent than if
the drugs are given iv-ly
Enterohepatic circulation
Drug in faeces
• Oral: due to billiary excretion or incomplete
absorption?
• Parenteral: Drug was excreted in the bile!
Enterohepatic circulation
“ The cycle in which the drug is absorbed,
excreted into the bile, & reabsorbed in
duodenum”
• Some drugs excreted as a glucoronide
conjugate will become hydrolized in the
gut back to the parent drug by the action
of a Beta-glucuronidase enzyme present
in the intestinal bacteria. Parent drug
becomes available for reabsorption