Drug Absorption, Distribution, Metabolism, Elimination - A

Drug Absorption, Distribution,
Metabolism, Elimination
Chapter 3
Physical/Chemical Properties of
Ability to Approach Receptors
Drug Mol’s  Receptors
• Bloodstream (cardiovascular system)
– Bulk flow transfer
– Fast, long-distance
– Chem nature of drug not impt
• Short distances
– Diffusion
– Chem properties impt
Chem Properties Impt to Diffusion
• Aqueous diffusion delivers most drug mol’s
• Rate of diffusion dependent on molec size
– Diffusion coeff = 1/ qMW
– BUT: Most drugs 200-1000 MW, so little
• Ability to cross barriers
– Cell membr’s mostly lipid
– Drug hydrophobicity impt
Absorption = Movement Across
Cell Barriers
• Cell membr’s separate aqueous
– Movement through cell involves traversing at
least 2 lipid bilayers
• Some tight junctions between cells
– Ex: CNS, placenta, testes
• Some freely permeable
– Ex: Liver, spleen
• Vascular endothelium differs in
Small Mol’s Cross Cell Membr’s
• Diff’n  lipid
• Diff’n  aqueous
pores traversing
lipid bilayer
– BUT most pores
too small to
accomm most
• Transmembr
carrier prot
• Pinocytosis
– Not impt for small
• Number mol’s crossing membr per unit
area in unit time; depends on
• Permeability coefficient (P)
– Diffusivity
• Diffusion coefficient
• Doesn’t differ much between drugs
– Solubility in membr
• Partition coefficient (solubility oil/solubility water)
• Most impt to pharmacokinetics
• Used as predictor of drug properties
pH and Ionization
• Many drugs are weak acids/bases
– Can be ionized, unionized
– Varies w/ pH of environment
• Acids release H+
– Strong: All H+ released
– Weak: Some H+ released
• Ka quantitates strength of acid
• Weak acid ionization (HA  H+ + A-)
– Ka = [H+][A-]/[HA]
– Negative log and rearrangement:
• Log [H+] = log Ka + log [A-]/[HA]
– pH = pKa + log [A-]/[HA]
• Henderson/Hasselbach equation
• pKa = pH when drug 50% dissoc’d
• Weak base ionization (BH+  H+ + B)
– Ka = [H+][B]/[BH+]
– Negative log and rearrangement
– pH = pKa + log [B]/[BH+]
• Rearrangement if known pH, pKa allows
deter’n ionized/unionized ratio at any pH
pH Differences between Body
• Environmental pH effects ability to release
H+ (ionization)
• Ionized species have low lipid solubility
– Most: uncharged can traverse cell membr’s
• So each environment’s pH effects drug
dist’n between them
– Ion trapping
–  Compartment equilibrium
Ex: Stomach  Blood
• Assume weak acid drug (HA) w/ pKa=6.0
• Assume [HA]=1.0
• Stomach pH=1.0
– 1.0-6.0=log [A-]/[HA]
– 1.0x10-5=[A-]
• Little ionized drug
• Blood pH=7.0
– 10=[A-]
• Much ionized drug
• Expect stomach-to-plasma traverse BUT not
Book ex: more basic drug (how do we know?)
Plasma  Digestive Tract
• Acidic drugs concent’d in high pH
– Site of highst dissoc’n H+ (ionization)
– Can’t traverse membr to escape
• Basic drugs concent’d in low pH
• Largest D pH between compartments 
largest D [drug]
– BUT not total impermeability
– AND not total equilib
– Most impt to gi, renal
Carrier Mediated Transport
• Specialized for physiologically impt mol’s
– Sugars, neurotransmitters, metals, etc
• Transmembr prot
– Binds mol(s)
– Changes conform’n
– Releases to other side of membr
• Diff kinetics than simple diffusion
– Can become saturated
– Subject to competition between ligands
• Two types of carriers allow
– Facilitated diff’n
• Along concent gradient
– Active transport
• Against gradient
• Cell uses chem energy
• Carriers impt pharmacologically
Renal tubule
Biliary tract
Blood-brain barrier
GI tract
• P-glycoprotein impt drug transporter
– Renal tubular cells, bile canaliculi, brain
Drug Administration
Two Major Routes
• Enteral
– Via gastrointestinal tract (gi)
• Oral
• Sublingual
• Buccal
• Parenteral
– Via injection
• IV
• IM
• Subcu
• Intrathecal
Oral Administration
• Convenient; includes most drugs
• Little absorption until small intestine
– Are most drugs weak acids or bases?
• Abs’n from small intestine
– Passive transfer dependent on
• Ionization
• Lipid solubility
– Some carrier-mediated transport
• Levodopa through carrier for phenylalanine
• Fluorouracil through carrier for pyrimidines
• Fe, Ca
• Rates abs’n after oral admin depend on
– Gi motility
• Some disorders  gastric stasis
• Some drugs affect motility (incr or decr)
• Meals
– Splanchnic blood flow
– Drug particle size/formulation
• Capsules/coated tablets
• Timed release formulations
– Physicochemical factors
• Tetracycline binds Ca  milk prevents abs’n
• Drug interactions
• Proportion of drug that passes into
systemic circ’n after oral admin
• Dependent on
– Absorption
– Local metab by small intestine enzymes
• Indiv pts’ physiology impt
– Activity intestinal metab enz’s
– pH variations
– Motility
• Differs w/ type dose (oral, IV)
– Oral dosing  further metab
• Book: First pass effect through liver
– = AUCoral/AUCIV x doseIV/doseoral
• AUC = Area Under Curve of drug plasma concent
vs. time
• “Bioequivalence” used to compare generic
drugs to patented
Other Types of Drug Admin
• Sublingual
– Impt when
• Rapid response req’d
• Drug unstable at gastric pH
• Drug rapidly metab’d by liver
– Pass straight into systemic circ’n
• Don’t enter liver portal system (so no first-pass
• Ex: glyceryl trinitrate relieves angina
– Metab  NO release
– NO act’s soluble guanylate cyclase (sim to ad
–  incr’d cGMP  act’n prot kinase G
–  biochem cascade in smooth muscle
–  dephosph’n myosin light chains,
sequestering Ca
–  vascular smooth muscle relaxation
• Also relaxes cardiac muscle
–  decr’d bp, so red’d preload, cardiac
• So decr’d cardiac O2 consumption
– Also redist’n coronary blood flow toward
ischemic cardiac areas
• Rectal
– Abs’n unreliable
– Often for local action
– Useful in pts vomiting, unable to take by
mouth (infants)
• Cutaneous
Local effect on skin req’d
Abs’n occurs  systemic effects
Suitable for lipid-soluble mol’s
Ex: estrogen patch
• Nasal sprays
– Abs’n through mucosa overlaying lymphoid
– Impt for drugs inact’d in gi
– Ex: peptide hormone analogs, ADH,
• Inhalation
Large surface area and high blood flow
No gi inact’n
BUT also route of elim’n
Ex: volatile, gaseous anesthetics
Ex: locally acting drugs
Ex: inhaled human insulin being tested
Admin by Injection
• Subcutaneous, intramuscular
– Faster than oral
– Rate abs’n depends on site admin, local blood
– Red’n or prolonging systemic action poss by
altering drug mol or prep’n or giving w/
another agent
• Intrathecal
Into subarachnoid space via lumbar puncture
Ex: regional anesthetics
Ex: cancer chemotherapeutics
Ex: antibiotics for NS infections
• Intravenous (IV) fastest, most certain
– Bolus  high concent R heart, lung, systemic
– Peak concent depends on rate injection
– Common ex: antibiotics, anesthetics
– Most uncomplicated to understand
distribution, pharmacokinetics
Distribution of Drugs in the Body
Experimental Finding
• Rates drug abs’n, dist’n, elim’n gen’ly directly
proportional to physio concent
• First order kinetics
– Rate varies w/ first power of concent
dC(t)/dt = -kEC(t)
where dC(t)/dt = rate change [drug]
kE = elimination constant
(neg sign due to decr [drug] w/ elim’n)
• Note: rate elim’n may be zero order (independent
of concentration)
– Ex: ethanol
Kinetics Meas’d w/ Single IV Dose
• Single bolus over 5-30 sec
• Periodic blood samples analyzed for [drug]
– Time ~0 – highest concent
• Dist’n drug in circulation  equilib
• Complete by sev passes through heart (sev min)
– Later time – concent decr’s due to
• Dist’n  tissues
• Dist’n  other body fluids
• Metab  other cmpds
• Excr’n unchanged drug (renal, biliary, lung)
• (Concent (y axis)
reflects free drug +
drug bound to
plasma prot’s)
• Conversion to log
concent  more
linear curve
– Non-linear portion
– dist’n phase (a
• Rapid decr
plasma concent
– Linear portion –
elimination phase
• Grad decr plasma
• Eq’n line for elim’n phase:
C(t) = C0e-kEt
– Where C(t) = Concent drug @ time (t)
C0 = Concent @ time 0
e = nat’l log base
kE = rate const for phase (elim’n rate const)
t = time
– Y int = C0; slope = -kE/2.3
• Can be used to deter rate dist’n when a
phase included
With Oral Admin…
• Plot differs in a phase
• Initial: [plasma] = 0
– Swallowing, dissolution, abs’n take time
• Rapid abs’n  rate b phase incr’s
– First order: rate incr w/ incr’d [drug]
• Peak concent at rate abs’n = rate elim’n
Body Fluid Compartments:
Sites of [Drug]
• Total body water=50-70% total body wt
• Intracell highest
• Extracell:
– Interstitial = between cells
– Plasma = blood + lymph
– Transcell = cerebrospinal, intraocular, synovial,
• Fat is also compartment
– BUT poorly perfused
• Dug mol’s exist ionized/unionized,
free/bound in each compartment
• Dist’n pattern for each drug dependent on
Membrane permeability/transport
Binding w/in compartment
pH partitioning
Fat/water partitioning
Specialized Compartment – Blood
Brain Barrier
• History: Ehrlich -- dyes injected IV stained
most tissues; brain unstained
• Contin layer endothelial cells w/ tight
– Non-brain – fenestrations
• Specific transport for small organics
• Safety buffer
• Throughout brain, spinal cord
– Except floor of hypothal, area postrema
• Inaccessible to many drugs unless high
lipid solubility
– BUT inflamm’n can disrupt integrity
– AND some peptides increase bbb
– Intrathecal injection sometimes
Volume of Distribution
• Vol fluid req’d to contain drug in body at
same concent as that present in plasma
• May indicate drug binding to plasma prot
or other tissue constituents
• Vd = D/C0
– Where Vd = vol dist’n (L)
D = dose w/ IV injection (mg)
C0 = blood concent @ 0 time (mg/L)
• Most impt:
free drug in
• Drug values
vary greatly
– Molecular
– More impt:
Drug Binding to Plasma Proteins
• Reflected in Vd
• If high binding, drug “trapped” in plasma
– High C0 on graph (Y reflects bound + unbound
– For Vd=D/C0, Vd very low (2-10L)
• Ex: warfarin (anticoagulant)
• If low binding, drug free to disperse 
– Low plasma concent (= low C0)
– Vd high (40,000 L)
• Ex: furosemide (diuretic)
• Plasma proteins that bind drugs
– Albumin impt to acidic drugs
• Most abundant plasma prot
– Not fully saturated
• Synth’d in liver
• Concent changes w/ disease, dysfunction
 a-acid glycoprotein impt to basic drugs
• Lower concent than albumin
• Varies among population
• Varies in individual if disease states
– Lipoprotein binding not well understood
• Varies w/ disease states
• Vol blood cleared of drug per time
• Describes efficiency of elim’n from body
– Sum of all types elim’n
• Renal
• Hepatic
• Organ
• Impt; independent of
– Vol dist’n
– Bioavailability
– Half-life
• Elim’n rate – quantity of drug removed
– Assume first order kinetics
• CLp = rate elim’n drug/plasma [drug]
Where CLp = total body removal from
plasma (p) (mL/min), when
rate elim’n (mg/min)
plasma concent (mg/mL)
• Useful clin’ly for dosage rate, if target
concent known
Half-Life (t1/2)
• Time nec for [drug] to decr by half
• Can be found from graph log C(t) vs. t
where C(t) = concent drug @ time t
• Mins – days
• Impt to deter’n multiple dosing regimen
• Dependent on clearance, vol dist’n
t1/2 = (0.693 x Vd)/CL
Drug Metabolism
Biotransform’n Drug Molecules
• Drug changed chem’ly  metabolite
– Prodrugs must be metab’d for act’n
• Chem alteration by enz rxn
• Gen’ly nonpolar, lipid-sol cmpds  more
polar, water-sol
– Now easier urinary excr’n
• Some metabolites active (or more active)
than parent drugs
– Ex: demethlyation diazepam  (less) active
agent but w/ longer ½ life than parent
• Drug metabolizing enz’s mostly in liver
• BUT most other tissues also can metabolize
Gi bacteria
• Four impt types chem rxns for drug metab
• Ox’n, conjugation most impt
• Partic enz’s carry out these rxns
Two Major Metabolism Types
• Phase I Reactions
– Catabolic
• Mostly ox’ns
– Functionalization:
• Intro reactive grp (ex: hydroxyl)
• Prod’s more chem’ly reactive, hydrophilic than
• Serves as pt chem attack for….
• Phase II Reactions
– Anabolic (synthetic)
– Involve conjugations rxns
• Attachment substituent
• Large, hydrophilic
• Liver major site Phase I, II rxns
– Metabolic enz’s embedded in smooth ER
• Microsomal
• Stereoselective
• Both types rxns  more polar, hydrophilic
Phase I Rxns
• Catalyzed by Cytochromes P450 (CYP’s)
– Enz superfamily
• 74 CYP gene families
• Differ in aa seq, inhibitors/inducers, specificity
– 3 main families impt to hepatic drug metab (CYP’s 1, 2, 3)
• CYP1A2 – a main enz
– Contains heme w/ Fe
• Redox capability
• Binds O2
– Assoc’d w/ NAD(P) reductase enz
• Allows metab many diff agents
• Most common to all substrates: lipophilicity
• Gen’l rxn: DH + NAD(P)H + H+ + O2
 DOH + NAD(P)+ + H2O
where DH = drug
NAD(P)H = red’d coenzyme
DOH = ox’d drug
NAD(P)+ = ox’d coenzyme
O2 = final electron acceptor
• Complicated cycle results in 1 O atom
added to drug, other O  water
– Free radical or iron-radical grps formed at
parts of cycle
• Highly reactive, dangerous
Fp = Flavin Protein Coenzyme (NADPH-P450 Reductase)
• Other metabolic rxns (some enz catalyzed)
include red’n, hydrolysis
– Alcohol dehydrogenase metab’s ethanol
– Monoamine oxidase metab’s many amines
• Some foods, other drugs, herbs,
environmental agents, inhibit/induce CYP’s
 change in metabolism drugs  change
drug activity
– Grapefruit juice, St. John’s wort inhibit drug
metab by inhib’n CYP enz’s
– Brusssels sprouts, cigarettes induce P450 enz’s
Phase II Reactions
• Attachment substituent grp on parent/
– Typically added @ hydroxyl, thiol, amino
– Substituent first “activated”
• Phosph’n
• Att’d to CoA
• S-Adenosyl methionine
• Rxn enzyme-catalyzed
• Product almost always inactive, less lipid
– Excr’d in urine, bile
• Common
Rates of Drug Metab
• Follow MM kinetics
– V = (Vmax[S])/KM + [S]
• In vivo, Vmax directly proportional to
– Can have competition between drugs metab’d
by same enz
– BUT most drugs found at concent’s << KM so
far below saturation of enz active sites
• Enzyme induction – synth of metabolic
enz’s stimulated
– Both microsomal and conjugating systems
– See incr’d metabolic activity
• Due to repeated exposure to
– Drugs
– Environmental chem’s
– Carcinogens
• May  decr’d drug activity OR incr’d
Figure 3-10 Example of enzyme induction. Zoxazolamine administered by intraperitoneal injection to rats. For induction studies,
phenobarbital or 3,4-benzo[a]pyrene was injected twice daily for 4 days before injection of zoxazolamine.
• Most thoroughly studied inducers – PAH’s
(env chem’s also found in cigarettes)
Bind nuclear receptors (Ah receptors)
Complexes bind response elements on DNA
 Promotion transcr’n CYP1A1 gene
• Book: Induction P450s by PAHs in
cigarette smoke  decr’d estradiol in
female smokers
First Pass Effect of Liver
• Liver site of much metab
– Amt abs’d >>> amt reaching systemic circ’n
– Impt to many drugs
• Much give much larger oral dose than
• Indiv variations in extent of first-pass effect
for partic drugs among population (so
Biliary Excr’n
• Liver may excrete drugs  bile
– Drug carrier system (P-glycoprotein) impt
• Bile duct carries  small intestine
• Glucuronides concent’d in bile
– At small intestine, enz’s cleave glucuronide 
active drug released, reabs’d
– Cycle repeated
– “Enterohepatic circulation”
–  “reservoir” of recirculating drug
Elimination from the Body
Renal Elimination
• Kidney clears some drugs very efficiently
(penicillin in single pass), others take many
passes through renal tubule for excr’n
• Glomerular filtration
– ~20% renal plasma flow filtered through
– MW < 20000 diffuse into glomerular filtrate
– Appreciable binding to albumin  decr’d
diffusion into filtrate
• Tubular secretion
– ~80% renal blood flow passes through
peritubular capillaries of prox tubule
– Two carriers transport drugs from blood in
capillaries  proximal renal tubule
• Carrier for acidic mol’s (including endogenous
• Carrier for basic mol’s
• Move against electrochem gradient
– Can achieve max drug clearance
– Movement of free drug mol’s out of plasma
pushes equilib toward freeing drug mol’s from
albumin  more free drug elim’d and more
drug dissoc’ng from albumin
• Diffusion across renal tubule
– Most water reabs’d from renal tubule
• Concentrates urine
– Highly lipophilic drugs can move across tubule
cell membr’s, reabs’d back into blood
– Highly polar drugs (low permeability) remain
in tubule
– pH change in urine  ionization  ion
trapping in urine  elimination
• Basic drugs more rapidly excr’d in acidic urine
One-Compartment Model
• Simplest kinetics
• Volume of distribution considered single, wellstirred compartment
Real Life is More Complicated…
Two Compartment Model
• Add repeated doses, saturating kinetics, other
physiological parameters: kinetics more difficult