K-BR.Ch4 Drug Metabolism -Terms

Induction and inhibition of drug metabolism

A large number of drugs alter their own metabolism and the metabolism of other drugs either by inducing the synthesis of larger amounts of the metabolizing enzymes (usually P450 enzymes in the liver) or by inhibiting those enzymes. Some drugs both inhibit (acutely) and induce (with chronic administration) drug metabolism

1A2 Benzo[a]pyrene (from tobacco smoke), carbamazepine, phenobarbital, rifampin, omeprazole

Acetaminophen, clozapine, haloperidol, theophylline, tricyclic antidepressants, (R)-warfarin

1A2 Cimetidine, fluoroquinolones, grapefruit juice, macrolides, isoniazid, zileuton

Acetaminophen, clozapine, haloperidol, theophylline, tricyclic antidepressants, (R)-warfarin

Glucuronidation

Acetaminophen, diazepam, digoxin, morphine, sulfamethiazole

2E1 Ethanol, isoniazid

Acetaminophen, enflurane, ethanol (minor), halothane

Sulfation

Acetaminophen, methyldopa

Drug Metabolism

All organisms are exposed to foreign chemical compounds (xenobiotics) in the air, water, and food. To ensure elimination of pharmacologically active xenobiotics as well as to terminate the action of many endogenous substances, evolution has provided metabolic pathways that alter such compounds' activity and their susceptibility to excretion.

Oxidations, P450 independent

Amine oxidation → Epinephrine Dehydrogenation → Chloral hydrate, ethanol

P-glycoprotein, MDR-1

An ATP-dependent transport molecule found in many epithelial and cancer cells. The transporter expels drug molecules from the cytoplasm into the extracellular space. In epithelial cells, expulsion is via the external or luminal face

3A4 Amiodarone, azole antifungals, cimetidine, clarithromycin, cyclosporine, diltiazem, erythromycin, fluoroquinolones, grapefruit juice, HIV protease inhibitors, metronidazole, quinine, SSRIs, tacrolimus

Antiarrhythmics, antidepressants, azole antifungals, benzodiazepines, calcium channel blockers, cyclosporine, delavirdine, doxorubicin, efavirenz, erythromycin, estrogens, HIV protease inhibitors, nefazodone, paclitaxel, proton pump inhibitors, HMG-CoA reductase inhibitors, rifabutin, rifampin, sildenafil, SSRIs, tamoxifen, trazodone, vinca alkaloids

3A4 Barbiturates, carbamazepine, corticosteroids, efavirenz, phenytoin, rifampin, pioglitazone, St. John's wort

Antiarrhythmics, antidepressants, azole antifungals, benzodiazepines, calcium channel blockers, cyclosporine, delavirdine, doxorubicin, efavirenz, erythromycin, estrogens, HIV protease inhibitors, nefazodone, paclitaxel, proton pump inhibitors, HMG-CoA reductase inhibitors, rifabutin, rifampin, sildenafil, SSRIs, tamoxifen, trazodone, vinca alkaloids

2D6 Amiodarone, cimetidine, quinidine, SSRIs

Antiarrhythmics, antidepressants, beta blockers, clozapine, flecainide, lidocaine, mexiletine, opioids

2C9 Amiodarone, chloramphenicol, cimetidine, isoniazid, metronidazole, SSRIs, zafirlukast

Barbiturates, celecoxib, chloramphenicol, doxorubicin, ibuprofen, phenytoin, chlorpromazine, steroids, tolbutamide, (S)-warfarin

2C9 Barbiturates, especially phenobarbital, phenytoin, primidone, rifampin

Barbiturates, celecoxib, chloramphenicol, doxorubicin, ibuprofen, phenytoin, chlorpromazine, steroids, tolbutamide, (S)-warfarin

Reductions

Chloramphenicol, clonazepam, dantrolene, naloxone

Acetylation

Clonazepam, dapsone, isoniazid, mescaline, sulfonamides

CYP isozymes

Cytochrome P450 enzyme species (eg, CYP2D6 and CYP3A4) that are responsible for much of drug metabolism. Many isoforms of CYP have been recognized

Glycine conjugation

Deoxycholic acid, nicotinic acid (niacin), salicylic acid

Major Concept

Description

2C19 Fluconazole, omeprazole, SSRIs

Diazepam, phenytoin, topiramate, (R)-warfarin

2C19 Carbamazepine, phenobarbital, phenytoin, rifampin

Diazepam, phenytoin, topiramate, tricyclic antidepressants, (R)-warfarin

Methylation

Dopamine, epinephrine, histamine, norepinephrine, thiouracil

CYP Family Induced (Important Inducers)

Drugs Whose Metabolism Is Induced

CYP Family Inhibited Inhibitors

Drugs Whose Metabolism Is Inhibited

Hydrolyses

Esters → Aspirin, clofibrate, procaine, succinylcholin Amides → Indomethacin, lidocaine, procainamide

Glutathione conjugation

Ethacrynic acid, reactive phase I metabolite of acetaminophen

Pharmacogenomic variation in drug metabolism

Genetic variations in drug metabolism undoubtedly occur for many drugs. Specific differences have been defined for (1) succinylcholine and similar esters, (2) procainamide and similar amines, and (3) a miscellaneous group that includes β blockers, antidepressants, and others (see Chapter 5)

Oxidations, P450 dependent

Hydroxylation → Amphetamines, barbiturates, phenytoin, warfarin N-dealkylation → Caffeine, morphine, theophylline O-dealkylation → Codeine N-oxidation Acetaminophen, nicotine S-oxidation → Chlorpromazine, cimetidine, thioridazine Deamination → Amphetamine, diazepam

Phase I reactions

Reactions that convert the parent drug to a more polar (water-soluble) or more reactive product by unmasking or inserting a polar functional group such as ´OH, ´SH, or ´NH2

Phase II reactions

Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate

Toxic metabolism

Some substances are metabolized to toxic molecules by drug-metabolizing enzymes. Important examples include methyl alcohol, ethylene glycol, and, at high doses or in the presence of liver disease, acetaminophen. See Figure 4-1 and Chapter 23

Enzyme induction

Stimulation of drug-metabolizing capacity; usually manifested in the liver by increased synthesis of smooth endoplasmic reticulum (which contains high concentrations of phase I enzymes)

Drug metabolism vs drug elimination

Termination of drug action requires either removal of the drug from the body (excretion) or modification of the drug molecule (metabolism) so that it no longer has an effect. Both methods constitute drug elimination, and both are very important in the clinical use of drugs. Almost all drugs (or their metabolites) are eventually excreted, but for many, excretion occurs only some time after they have been metabolized to inactive products

High-Yield

Terms to Learn

Examples of phase II drug-metabolizing reactions-Reaction Type

Typical Drug Substrates

Reaction Type (phase I drug-metabolizing reactions)

Typical Drug Substrates