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 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
Metabolite with modified activity Inactive metabolite

Phase II
Conjugate
Conjugate

Drug

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 product

Parent drug binds ferric state of enzyme.

Note the Fe2+ / Fe3+ valence transitions.

Electrons 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 Plasma Level Zoxazolamine (mg/ml)

No induction Phenobarbital (Classic barbiturate induction effect) Benzopyrene induction

10

(Generated from grilling meat)

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.
2. 3. 4.

Oxidation
Reactive Intermediate Glutathione Conjugation Hepatic Cell Death

Acetominophen Metabolism
Ac-glucuronide Ac Ac-sulfate Cytochrome P-450 Reactive electrophilic compound (Ac*)

Good

GSH GS-Ac* Ac*-protein

Bad

Ac-mercapturate

Hepatic cell death

Elimination Of Drugs
Metabolism: Excretion: Liver 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)
Active Transport: Uric acid, glucose, amino acids...

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
2

Portal vein
1

Common bile duct

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)

Age and Hepatic Metabolic Activity

Hepatic drug metabolic activity

Birth

Puberty

Adulthood

Old age

Age

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 27 ml/min Clearance %unbound 2.2 in plasma 106 14 4.7

Cardivascular disease Hepatic perfusion decreased the clearance reduced Alter the concentration of drug binding protein (AAG) Affects drug metabolism in the liver

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. efficacy decrease, adverse/toxicity effect increase Inhibit directly. accumulation to toxic concentration Renal tubular secretion: Inhibit secretion of weak acids (pH .) Inhibit secretion of weak bases (pH ) *Phenobarbital, phenytoin, phenylbutazone.

*Cimetidine, carbidopa, MAOI, disulfiram.

*Penicillin, salicylates.

*Cimetidine.

 Drug excretion modify pH urine (ammonium chlorida- acidify, sodium bicarbonate alkalize) alter GFR alter RBF inhibit transport in hepatobiliary syst/ bile blood flow

Single-compartment model

ka Absorption

Vd
Body

ke 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