Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 4. Drug Metabolism

Drug Metabolism: Introduction

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 resulted in metabolic pathways that alter their activity and their susceptibility to excretion.

High-Yield Terms to Learn

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 CYP isozymes Cytochrome P450 enzyme species (eg, CYP2D and CYP3A4) that are responsible for much of drug metabolism. Many isoforms of CYP have been recognized 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) 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

The Need for Drug Metabolism

Many cells that act as portals for entry of external molecules into the body (eg, pulmonary epithelium, intestinal epithelium) contain transporter molecules (MDR [P-glycoprotein] family, MRP family, others) that expel unwanted molecules immediately after absorption. However, some foreign molecules evade these gatekeepers and are absorbed. Therefore, all higher organisms, especially terrestrial animals, require mechanisms for ridding themselves of toxic foreign molecules after they are absorbed, as well as mechanisms for excreting undesirable substances produced within the body. Biotransformation of drugs is one such process. It is an important mechanism by which the body terminates the action of many drugs but in some cases, it serves to activate prodrugs. Most drugs are relatively lipid soluble as given, a characteristic needed for absorption across membranes. The same property would result in very slow removal from the body because the unchanged molecule would also be readily reabsorbed from the urine in the renal tubule. The body hastens excretion by transforming many drugs to less lipid-soluble, less readily reabsorbed forms.

Types of Metabolic Reactions

Phase I Reactions

Phase I reactions include oxidation (especially by the cytochrome P450 group of enzymes, also called mixed-function oxidases), reduction, deamination, and hydrolysis. Examples are listed in Table 4-1. These enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver. They are not highly selective in their substrates, so a relatively small number of P450 isoforms are responsible for the metabolism of thousands of drugs. Of the drugs metabolized by phase I cytochrome P450s, approximately 75% are metabolized by just two: CYP3A4 or CYP2D6. Nevertheless, some selectivity can be detected, and optical enantiomers, in particular, are often metabolized at different rates.

TABLE 4-1 Examples of phase I drug-metabolizing reactions.

Reaction Type Typical Drug Substrates 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 Oxidations, P450 independent Amine oxidation Epinephrine Dehydrogenation Chloral hydrate, ethanol Reductions Chloramphenicol, clonazepam, dantrolene, naloxone Hydrolyses Esters Aspirin, clofibrate, procaine, succinylcholine Amides Indomethacin, lidocaine, procainamide

Phase II Reactions

Phase II reactions are synthetic reactions that involve addition (conjugation) of subgroups to -OH, -NH2, and -SH functions on the drug molecule. The subgroups that are added include glucuronate, acetate, glutathione, glycine, sulfate, and methyl groups. Most of these groups are relatively polar and make the product less lipid-soluble than the original drug molecule. Examples of phase II reactions are listed in Table 4-2. Like phase I enzymes, phase II enzymes are not very selective. Drugs that are metabolized by both routes may undergo phase II metabolism before or after phase I.

TABLE 4-2 Examples of phase II drug-metabolizing reactions.

Reaction Type Typical Drug Substrates Glucuronidation Acetaminophen, diazepam, digoxin, morphine, sulfamethiazole Acetylation Clonazepam, dapsone, isoniazid, mescaline, sulfonamides Glutathione conjugation Ethacrynic acid, reactive phase I metabolite of acetaminophen Glycine conjugation Deoxycholic acid, nicotinic acid (niacin), salicylic acid Sulfation Acetaminophen, estrone, methyldopa Methylation Dopamine, epinephrine, histamine, norepinephrine, thiouracil

Adapted, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.

Sites of Drug Metabolism

The most important organ for drug metabolism is the liver. The kidneys play an important role in the metabolism of some drugs. A few drugs (eg, esters) are metabolized in many tissues (eg, liver, blood, intestinal wall) because of the broad distribution of their enzymes.

Determinants of Biotransformation Rate

The rate of biotransformation of a drug may vary markedly among different individuals. This variation is most often due to genetic or drug-induced differences. For a few drugs, age or disease-related differences in drug metabolism are significant. In humans, gender is important for only a few drugs. (First-pass metabolism of alcohol is greater in men than in women.) On the other hand, a variety of drugs may induce or inhibit drug-metabolizing enzymes to a very significant extent. Smoking is a common cause of enzyme induction in the liver and lung and may increase the metabolism of some drugs. Because the rate of biotransformation is often the primary determinant of clearance, variations in drug metabolism must be considered carefully when designing or modifying a dosage regimen.

Genetic Factors

Because recent advances in genomic techniques are making it possible to screen for a huge variety of polymorphisms, it is expected that pharmacogenomics will become an important part of patient evaluation in the future, determining both drug choice and drug dosing. Several drug-metabolizing systems have already been shown to differ among families or populations in genetically determined ways. However, screening for these variants has not yet become common.

Hydrolysis of Esters

Succinylcholine is an ester that is metabolized in a phase I reaction by plasma cholinesterase ("pseudocholinesterase" or butyrylcholinesterase). In most persons, this process occurs very rapidly, and a single dose of this neuromuscular-blocking drug has a duration of action of about 5 min. Approximately 1 person in 2500 has an abnormal form of this enzyme that metabolizes succinylcholine and similar esters much more slowly. In such persons, the neuromuscular paralysis produced by a single dose of succinylcholine may last many hours.

Acetylation of Amines

Isoniazid and some other amines such as hydralazine and procainamide are metabolized in a phase II reaction by N-acetylation. People who are deficient in acetylation capacity, termed slow acetylators, may have prolonged or toxic responses to normal doses of these drugs. Slow acetylators constitute about 50% of white and African American persons in the United States and a much smaller percentage of Asian and Inuit (Eskimo) populations. The slow acetylation trait is inherited as an autosomal recessive gene.

Oxidation

The rate of phase I oxidation of debrisoquin, sparteine, phenformin, dextromethorphan, metoprolol, and some tricyclic antidepressants by certain P450 isozymes has been shown to be genetically determined.

Other Drugs

Coadministration of certain agents may alter the disposition of many drugs. Mechanisms include the following:

Enzyme Induction

Induction usually results from increased synthesis of cytochrome P450-dependent drug-oxidizing enzymes in the liver as well as the cofactor, heme. Several cytoplasmic drug receptors have been identified that result in activation of the genes for P450 isoforms. Many isozymes of the P450 family exist, and inducers selectively increase subgroups of isozymes. Common inducers of a few of these isozymes and the drugs whose metabolism is increased are listed in Table 4-3. Several days are usually required to reach maximum induction; a similar amount of time is required to regress after withdrawal of the inducer. The most common strong inducers of drug metabolism are carbamazepine, phenobarbital, phenytoin, and rifampin.

TABLE 4-3 A partial list of drugs that significantly induce P450-mediated drug metabolism in humans.

CYP Family Induced Important Inducers Drugs Whose Metabolism Is Induced 1A2 Benzo[a]pyrene (from tobacco smoke), carbamazepine, Acetaminophen, clozapine, haloperidol, theophylline, phenobarbital, rifampin, omeprazole tricyclic antidepressants, (R)-warfarin 2C9 Barbiturates, especially phenobarbital, phenytoin, Barbiturates, celecoxib, chloramphenicol, doxorubicin, primidone, rifampin ibuprofen, phenytoin, chlorpromazine, steroids, tolbutamide, (S)-warfarin 2C19 Carbamazepine, phenobarbital, phenytoin, rifampin Diazepam, phenytoin, topiramate, tricyclic antidepressants, (R)-warfarin 2E1 Ethanol, isoniazid Acetaminophen, enflurane, ethanol (minor), halothane 3A4 Barbiturates, carbamazepine, corticosteroids, efavirenz, Antiarrhythmics, antidepressants, azole antifungals, phenytoin, rifampin, pioglitazone, St. John's wort 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

Enzyme Inhibition

A few common inhibitors and the drugs whose metabolism is diminished are listed in Table 4-4. The most likely inhibitors of drug metabolism to be involved in serious drug interactions are amiodarone, cimetidine, furanocoumarins present in grapefruit juice, azole antifungals, and the HIV protease inhibitor ritonavir. Suicide inhibitors are drugs that are metabolized to products that irreversibly inhibit the metabolizing enzyme. Such agents include ethinyl estradiol, norethindrone, spironolactone, secobarbital, allopurinol, fluroxene, and propylthiouracil. Metabolism may also be decreased by pharmacodynamic factors such as a reduction in blood flow to the metabolizing organ (eg, propranolol reduces hepatic blood flow).

TABLE 4-4 A partial list of drugs that significantly inhibit P450-mediated drug metabolism in humans.

CYP Family Inhibited Inhibitors Drugs Whose Metabolism Is Inhibited 1A2 Cimetidine, fluoroquinolones, grapefruit juice, macrolides, isoniazid, zileuton Acetaminophen, clozapine, haloperidol, theophylline, tricyclic antidepressants, (R)-warfarin 2C9 Amiodarone, chloramphenicol, cimetidine, isoniazid, metronidazole, SSRIs, zafirlukast Barbiturates, celecoxib, chloramphenicol, doxorubicin, ibuprofen, phenytoin, chlorpromazine, steroids, tolbutamide, (S)-warfarin 2C19 Fluconazole, omeprazole, SSRIs Diazepam, phenytoin, topiramate, (R)-warfarin 2D6 Amiodarone, cimetidine, quinidine, SSRIs Antiarrhythmics, antidepressants, beta-blockers, clozapine, flecainide, lidocaine, mexiletine, opioids 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

SSRIs, selective serotonin reuptake inhibitors.

Inhibitors of Intestinal P-Glycoprotein

MDR-1, also known as P-glycoprotein (P-gp), has been identified as an important modulator of intestinal drug transport and usually functions to expel drugs from the intestinal mucosa into the lumen, thus contributing to presystemic elimination. (P-gp and other members of the MDR family are also found in the blood-brain barrier and in drug-resistant cancer cells.) Drugs that inhibit intestinal P-gp mimic drug metabolism inhibitors by increasing bioavailability; coadministration of P-gp inhibitors may result in toxic plasma concentrations of drugs given at normally nontoxic dosage. P-gp inhibitors include verapamil, mibefradil (a calcium channel blocker no longer on the market), and furanocoumarin components of grapefruit juice. Important drugs that are normally expelled by P-gp (and are therefore potentially more toxic when given with a P-gp inhibitor) include digoxin, cyclosporine, and saquinavir.

Toxic Metabolism

Drug metabolism is not synonymous with drug inactivation. Some drugs are converted to active products by metabolism. If these products are toxic, severe injury may result under some circumstances. An important example is acetaminophen when taken in large overdoses (Figure 4-1). Acetaminophen is conjugated to harmless glucuronide and sulfate metabolites when it is taken in recommended doses by patients with normal liver function. If a large overdose is taken, however, the phase II metabolic pathways are overwhelmed, and a P450-dependent system converts some of the drug to a reactive intermediate (N-acetyl-p-benzoquinoneimine). This intermediate is conjugated with glutathione to a third harmless product if glutathione stores are adequate. If glutathione stores are exhausted, however, the reactive intermediate combines with sulfhydryl groups on essential hepatic cell proteins, resulting in cell death. Prompt administration of other sulfhydryl donors (eg, acetylcysteine) may be life-saving after an overdose. In severe liver disease, stores of glucuronide, sulfate, and glutathione may be depleted, making the patient more susceptible to hepatic toxicity with near-normal doses of acetaminophen. Enzyme inducers (eg, ethanol) may increase acetaminophen toxicity because they increase phase I metabolism more than phase II metabolism, thus resulting in increased production of the reactive metabolite.

FIGURE 4-1

Metabolism of acetaminophen (Ac) to harmless conjugates or to toxic metabolites. Acetaminophen glucuronide, acetaminophen sulfate, and the mercapturate conjugate of acetaminophen all are nontoxic phase II conjugates. Ac* is the toxic, reactive phase I metabolite. Transformation to the reactive metabolite occurs when hepatic stores of sulfate, glucuronide, and glutathione (GSH, Gs) are depleted or overwhelmed or when phase I enzymes have been induced.

Checklist

When you complete this chapter, you should be able to:

 List the major phase I and phase II metabolic reactions.

 Describe the mechanism of hepatic enzyme induction and list 3 drugs that are known to cause it.

 List 3 drugs that inhibit the metabolism of other drugs.

 List 3 drugs for which there are well-defined, genetically determined differences in metabolism.

 Describe some of the effects of smoking, liver disease, and kidney disease on drug elimination.

Describe the pathways by which acetaminophen is metabolized (1) to harmless products if normal doses are taken and (2) to hepatotoxic products if an overdose is taken.

Chapter 4 Summary Table

Major Concept Description 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 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 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



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