Drug Elimination

Termination of Drug Action

 Termination Of Drug Action

• Metabolism (Biotransformation):

Anabolic and Catabolic Reactions

• Excretion

• Redistribution
 Drug Biotransformation

• Usually inactivates the drug.

• Can generate active metabolite (PRODRUG)
• Can generate toxic metabolite (isoniazid).
• Often generates polar, highly ionized metabolites.
• Conversion rate influences pharmacological activity.
• Some drugs are eliminated unchanged (digoxin).
Liver Metabolism
 Phase I and Phase II
Metabolic Reactions

These are general categories of

reactions and occur in no particular
order.
 Biotransformation of Major
Functional Groups
• (-OH) oxidation, methylation, glucuronide
conjugation, sulfate conjugation.

• (-COOH) oxidation, glucuronide conjugation,

glycine conjugation.

• (-NH2) deamination (and aldehyde formation),

glucuronide conjugation, methylation.
• Phase I “functionalization” reactions
(oxidation, reduction, hydrolysis) introduce or
expose a functional group on the parent
compound  result in loss of pharmacological
activity

• Phase II conjugation reactions lead to

covalent linkage of a functional group on the
parent drug or phase I metabolite with
endogenously derived glucuronic acid, sulfate,
methyl, glutathione, amino acids, acetate, etc
 result in highly polar conjugates
Phase I and Phase II Metabolic
Reactions

Absorption Metabolism Excretion

Phase I Phase II

Metabolite with
modified activity
Conjugate
Drug
Inactive metabolite Conjugate

Lipophilic Hydrophilic
 Phase I Reactions

Dominated by cytochrome P450

enzymes
Cytochrome P450 Mixed Function
Oxidases (MFOs)
• Smooth endoplasmic reticulum
(microsomes)
• Requires molecular oxygen, NADPH,
cytochrome P450 (hemoprotein),
cytochrome P450 reductase (flavoprotein).
• Hydroxylations
• N-, O-, S-dealkylations
• Deamination, desulfuration, dehalogenation
• Susceptible to induction
Families of Cytochrome P450
Enzymes (“CYPs”) are Based
on Amino Acid Sequence
Similarities
Estimated Contribution of Phase I and
Phase II Enzymes to Drug Metabolism
 Mechanism of Drug
Oxidation in the
Cytochrome P450 Cycle
 Reaction
Parent drug
product binds ferric
state of
enzyme.
Note the
Fe2+ / Fe3+
valence Electrons
transitions. from
NADPH via
reductase

Molecular
oxygen
 NADPH

Reductase

Cytochrome P450
 Some Drugs Stimulate and Some
Inhibit the drug metabolizing enzymes

• Stimulation is via induction, which means an

increase in enzyme synthesis (oxidation,
reduction, glucoronide formation).
• Phenobarbital and polycyslic aromatic
hydrocarbon (cigarette smoke) inducers
• Inhibition is via competition, prodrug
inhibition or a decrease in the activity of
existing enzyme.
• Cimetidine  inhibitor
 Enzyme Induction

100 No induction
Zoxazolamine (mg/ml)
Plasma Level

Phenobarbital (Classic barbiturate

induction effect)
10

Benzopyrene (Generated from

induction grilling meat)
1
Time (hrs)
 Other Types Of Phase I Metabolic
Reactions

• Nonmicrosomal oxidations: alcohol

dehydrogenase, xanthine oxidase.
• Microsomal / nonmicrosomal reductions
• Hydrolysis (amidases, esterases)
 Phase II Conjugation Reactions

• Glucuronidation (UDP glucuronosyltransferases)

• Glutathione (glutathione S-transferases)
• Amino acid (glycine, glutamine)
• Sulfate (sulfotransferases)
• Acetylation (N-acetyltransferases)
• Methylation (methyltransferases)
Nonpolar Polar

Very Polar
 ACETAMINOPHEN
METABOLISM

1. Oxidation
2. Reactive Intermediate
3. Glutathione Conjugation
4. Hepatic Cell Death
Acetominophen Metabolism

Ac-glucuronide Ac Ac-sulfate
Cytochrome P-450

Reactive electrophilic
compound (Ac*)

Good GSH Bad

Ac*-protein
GS-Ac*

Hepatic cell death

Ac-mercapturate
 Elimination Of Drugs

• Metabolism: Liver

• Excretion: Kidney
Liver (bile)
Lungs
Kidney Excretion
 Renal Excretion of Drugs

• Filtration (Glomerulus)
• Secretion - Active Transport (Tubule)
– Transporter for Organic Acids
– Transporter for Organic Bases
• Reabsorption - Passive Transport
(Tubule)
 Diagram of Nephron

Filtration :

Active secretion

Passive reabsorption
 Glomerular Filtration

• Only unbound drug is filtered.

• Plasma Protein Binding of drug prevents
filtration: Thyroxine is 99% bound.
• Molecular Size:
– Albumin (70,000) is not filtered.
– Inulin (5,500) is freely filtered; can be
used to estimate GFR.
 Tubular Secretion

Active Transport
• Organic Acids (inhibited by probenecid)
• Organic Bases
• No effect of protein binding on this process
• The clearance of drug eliminated by tubular
secretion is a function of renal blood flow
 Tubular Reabsorption

• Passive Transport:
– pH, concentration, size, lipid solubility,
ionization.
– acid urine favors reabsorption of weak
acid, basic urine favors reabsorption of
weak base.
– pH urine is affected by diet,drugs, diurnal,
condition of patients (respiratory and
metabolic acidosis)
 Other aspects….
amphetamine (weak base, pKa 10)
– its actions can be prolonged by
ingesting bicarbonate to alkalinize the
urine...
– this will increase the fraction of
amphetamine in non-ionized form,
which is readily reabsorbed across the
luminal surface of the kidney
nephron...
– in overdose, you may acidify the urine
to increase kidney clearance of
amphetamine.
• Others
– Bile
– Lung
– Feces
– Saliva
– Sweat
– Milk
 Enterohepatic Cycle

Liver 3
2

Portal vein Common bile duct

1 4

Small intestine
 Pulmonary Excretion

Factors:

– Plasma solubility of drug

– Cardiac output
– Respiration
 Factors affecting drug metabolism

• reversible binding to plasma proteins

• localization of drugs (e.g., fat)
• hepatic blood flow
• Age
• genetics-related deficiency or alteration in drug
metabolizing enzyme (e.g., acetylator,
pseudocholinesterase deficiency and succinylcholine)
• pathology
• inhibition / inductionof drug metabolizing enzyme (e.g.,
by erythromycin, phenobarbital)
• Diet (carb-protein, vegetables, charcoal-broiled beef)
• Enviromental chemicals (alcohol, cigarette smoking,
other chemicals)
 Pharmacokinetics variability-age-
pediatric

• ABSORPTION
• Gastrointestinal pH changes
• Gastric emptying
• Gastric enzymes
• Bile acids & biliary function
• Gastrointestinal flora
• Formula/food interaction
 Pharmacokinetics variability-age-
pediatric

• DISTRIBUTION
• Body Composition
–  total body water & extracellular fluid
–  adipose tissue & skeletal muscle
• Protein Binding
– albumin, bilirubin, 1-acid glycoprotein
• Tissue Binding
– compositional changes
 Age and Hepatic Metabolic
Activity

Hepatic drug
metabolic activity

Birth Puberty Adulthood Old age

Age
 Pharmacokinetics variability-age-
pediatric

• Glomerular filtration matures in relation to

age, adult values reached by 3 yrs of age
• Neonate = decreased renal blood flow,
glomerular filtration, & tubular function
yields prolonged elimination of medications
• Aminoglycosides, cephalosporins,
penicillins = longer dosing interval
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY

START LOW…..GO SLOW

 Pharmacokinetics variability-age-
PREGNANCY

• Gastric emptying and motility

• Glomerular filtration and
creatinine clearamce
• Metabolism
 Pharmacokinetics variability-age-
GENETIC

• Polymorphism acetylation
• Polymorphism oxidation
 Pharmacokinetics variability-disease

Renal disease
• A linear relationship between the renal
clearance of a drug and creatinine clearance
• A linear relationship between half life (t1/2)
of a drug and creatinine clearance
t1/2= 0.693/K
K= (A/V) creatinine clearance + (non renal
clearance/V)
 reducing dosage , lengthening the dosing
interval
• Hemodialysis  drug removal during
hemodialysis
• Some clinically important active or toxic
drug metabolite accumulate in renal failure
• The regeration of parent drug from
glucoronide conjugates that when its
elimination is impared
• Impaired drug binding (result of decreased
serum albumin and an accumulation of
endogenous inhibitors)
Liver disease
• The effects on drug metabolizing
enzymes, drug binding, hepatic blood
flow
Half life 27 hr 106
Clearance 27 ml/min 14
%unbound 2.2 4.7
in plasma
Cardivascular disease

• Hepatic perfusion decreased  the

clearance reduced
• Alter the concentration of drug
binding protein (AAG)
• Affects drug metabolism in the liver
 Effect of Disease on Drug
Disposition
• Absorption
– PO/NG administered drugs may have altered absorption
due to:
• Alterations in pH
• Edema of GI mucosa
• Delayed or enhanced gastric emptying
• Alterations in blood flow
• Presence of an ileus
• Coadministration with formulas (I.e. Phenytoin)
 Effect of Disease on Drug
Disposition
• Drug distribution may be affected:
– Altered organ perfusion due to hemodynamic
changes
• May effect delivery to site of action, site of
metabolism and site of elimination
• Inflammation and changes in capillary permeability
may enhance delivery of drug to a site
– Hypoxemia affecting organ function
• Altered hepatic function and drug metabolism
 Effect of Disease on Drug
Disposition
– Alterations in protein synthesis
• If serum albumin and other protein levels are low,
there is altered Vd of free fraction of drugs that
typically are highly protein bound therefore a higher
free concentration of drug
– Substrate deficiencies
• Exhaustion of stores
• Metabolic stress
 Pharmacokinetic Interactions:
• Gut Absorption: binding/chelation, gastric
emptying, gastrointestinal motility
(Anticholinergics, antacide/feroous
sulphate-tetracyclin etc)

• Plasma Protein Binding

Strongly bound drugs displace more weakly
bound drugs.
Drug Interactions Related to Protein
Binding

Moderately bound drugs (e.g., tolbutamide,

methotrexate, warfarin) are displaced by
strongly bound drugs (salicylates,
sulfonamides), which could lead to:
hypoglycemia, blood dyscrasias, and
hemorrhage, respectively, due to elevated
free concentrations of the displaced drugs.
Plasma protein
binding

Metabolic
enzyme
induction or
inhibition

GI absorption
 Pharmacokinetic Interactions:
Liver metabolism:
Enhance via induction. *Phenobarbital, phenytoin,
 efficacy decrease, phenylbutazone.
adverse/toxicity
effect increase
*Cimetidine, carbidopa,
MAOI, disulfiram.
Inhibit directly.
 accumulation to
toxic concentration
*Penicillin, salicylates.
Renal tubular secretion:
Inhibit secretion of
weak acids (pH ….)
*Cimetidine.
Inhibit secretion of
weak bases (pH …)
• Drug excretion
modify pH urine (ammonium chlorida-
acidify, sodium bicarbonate – alkalize)
 alter GFR
 alter RBF
 inhibit transport in hepatobiliary
syst/ bile blood flow
 Liver Clearance

• Extraction Ratio (ER): the extent to which a

drug is cleared from blood in one liver
passage.
• High ER (close to 1, e.g., propranolol,
meperidine). In this case, overall liver
extraction of the drug is dependent on liver
blood flow.
• Low ER (near 0.1, e.g., warfarin, diazepam,
phenytoin). In this case, changes in liver
blood flow are less critical.
Volume of distribution (Vd) relates
the amount of drug in the body to the
plasma concentration of drug (C).

total drug in body (mg)

Vd = ------------------------------
plasma conc. (mg/ml)
 • Clearance (CL): the measurement of
blood cleared of the drug by
elimination per unit time (as in units
of mL/sec). It and the volume of
distribution (Vd) create the
dependent variable T1/2. They are
related by the following formula:

T1/2 = 0.693Vd/CL

T1/2 = time required to reduce the concentration

by 50%
 Sum of all process
contributing to dis-
appearance of drug
from plasma

Drug in plasma at Drug concentration

concentration of 2 mg/ml in plasma is less after
each pass through
elimination/metabolism
process

Drug molecules disappearing from

plasma at rate of 400 mg/min

400 mg/min
CL = = 200 ml/min
2 mg/ml
Single-compartment model

ka Vd ke

Absorption Body Elimination

C = D/Vd or Vd = D/C
 Single compartment model: no
absorption, first-order elimination
Multicompartment models
• combine kinetics of redistribution and
elimination
• provide best description of drugs with high
lipid solubility and drugs given
intravenously
Two-compartment model