Chapter 4: Drug Metabolism

Many cells in tissues that act as portals for entry of external molecules into the body (eg, pulmonary epithelium, intestinal epithelium) contain transporter molecules (MDR family [P-glycoproteins], MRP family, others) that expel unwanted molecules immediately after absorption. However, many 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. 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.

A. 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 of phase I drug substrates 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 able to metabolize thousands of drugs. Of the drugs metabolized by phase I cytochrome P450s, approximately 75% are metabolized by just two: CYP3A4/5 or CYP2D6. CYP3A4 and CYP3A5 alone are responsible for the metabolism of approximately 50% of drugs. Nevertheless, some selectivity can be detected, and optical enantiomers, in particular, are often metabolized at different rates.

B. 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.

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 wide distribution of their enzymes.

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 ethanol 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.

A. Genetic Factors

Several drug-metabolizing systems have long been known to differ among families or populations in genetically determined ways. 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 near future, influencing both drug choice and drug dosing (see Chapter 5).

B. Effects of Other Drugs

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

1. Enzyme induction

Induction (increased rate and extent of metabolism) usually results from increased synthesis of cytochrome P450 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. Drugs and other xenobiotics that increase enzyme activity are known as inducers. Many isozymes of the P450 family exist, and most inducers selectively increase one or more 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.

2. Enzyme inhibition

A few common inhibitors and the drugs whose metabolism is diminished are listed in Table 4–4. The inhibitors of drug metabolism most likely 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).

3. Inhibitors of intestinal P-glycoprotein

MDR-1, also known as P-glycoprotein (P-gp), is an important modulator of intestinal drug transport and usually functions to expel drugs from the intestinal mucosa into the lumen, thus contributing to presystemic (first pass) 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.

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 phase I 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.

Questions 1–2. You are planning to treat chronic major depression in a 35-year-old patient with recurrent suicidal thoughts. She has several comorbid conditions that require drug therapy. You are concerned about drug interactions caused by changes in drug metabolism in this patient.

1. Drug metabolism in humans usually results in a product that is

   • (A) Less lipid soluble than the original drug

   • (B) More likely to distribute intracellularly

   • (C) More likely to be reabsorbed by kidney tubules

   • (D) More lipid soluble than the original drug

   • (E) Less water soluble than the original drug

2. If therapy with multiple drugs causes induction of drug metabolism in your depressed patient, it will

   • (A) Be associated with increased smooth endoplasmic reticulum

   • (B) Be associated with increased rough endoplasmic reticulum

   • (C) Be associated with decreased enzymes in the soluble cytoplasmic fraction

   • (D) Require 3–4 months to reach completion

   • (E) Be irreversible

3. Which of the following factors is likely to increase the duration of action of a drug that is metabolized by CYP3A4 in the liver?

   • (A) Chronic administration of rifampin during therapy with the drug in question

   • (B) Chronic therapy with amiodarone

   • (C) Displacement from tissue-binding sites by another drug

   • (D) Increased cardiac output

   • (E) Chronic administration of carbamazepine

4. Reports of cardiac arrhythmias caused by unusually high blood levels of 2 antihistamines, terfenadine and astemizole, led to their removal from the market. Which of the following best explains these effects?

   • (A) Concomitant treatment with rifampin

   • (B) Use of these drugs by chronic alcoholics

   • (C) Use of these drugs by chronic smokers

   • (D) Treatment of these patients with ketoconazole, an azole antifungal agent

5. Which of the following agents, when used in combination with other anti-HIV drugs, permits dose reductions?

   • (A) Cimetidine

   • (B) Efavirenz

   • (C) Ketoconazole

   • (D) Procainamide

   • (E) Quinidine

   • (F) Ritonavir

   • (G) Succinylcholine

   • (H) Verapamil

6. Which of the following drugs may inhibit the hepatic microsomal P450 responsible for warfarin metabolism?

   • (A) Amiodarone

   • (B) Ethanol

   • (C) Phenobarbital

   • (D) Procainamide

   • (E) Rifampin

7. Which of the following drugs, if used chronically, is most likely to increase the toxicity of acetaminophen?

   • (A) Cimetidine

   • (B) Ethanol

   • (C) Ketoconazole

   • (D) Procainamide

   • (E) Quinidine

   • (F) Ritonavir

   • (G) Succinylcholine

   • (H) Verapamil

8. Which of the following drugs has higher first-pass metabolism in men than in women?

   • (A) Cimetidine

   • (B) Ethanol

   • (C) Ketoconazole

   • (D) Procainamide

   • (E) Quinidine

   • (F) Ritonavir

   • (G) Succinylcholine

   • (H) Verapamil

9. Which of the following drugs is an established inhibitor of P-glycoprotein (P-gp) drug transporters?

   • (A) Cimetidine

   • (B) Ethanol

   • (C) Ketoconazole

   • (D) Procainamide

   • (E) Quinidine

   • (F) Ritonavir

   • (G) Succinylcholine

   • (H) Verapamil

10. Which of the following cytochrome isoforms is responsible for metabolizing the largest number of drugs?

    • (A) CYP1A2

    • (B) CYP2C9

    • (C) CYP2C19

    • (D) CYP2D6

    • (E) CYP3A4

1. Biotransformation usually results in a product that is less lipid-soluble. This facilitates elimination of drugs that would otherwise be reabsorbed from the renal tubule. The answer is A.

2. The smooth endoplasmic reticulum, which contains the mixed-function oxidase drug-metabolizing enzymes, is selectively increased by inducers. The answer is A.

3. Rifampin and carbamazepine can induce drug-metabolizing enzymes and thereby may reduce the duration of drug action. Displacement of drug from tissue may transiently increase the intensity of the effect but decreases the volume of distribution. Amiodarone is recognized as an inhibitor of P450 and may decrease clearance of drugs metabolized by CYP2C9, CYP2D6, and CYP3A4. The answer is B.

4. Treatment with rifampin and chronic alcohol use are associated with increased drug metabolism and lower, not higher, blood levels. Ketoconazole, itraconazole, erythromycin, and some substances in grapefruit juice slow the metabolism of certain older non-sedating antihistamines (Chapter 16). The answer is D.

5. Ritonavir inhibits hepatic drug metabolism, and its use at low doses in combination regimens has permitted dose reductions of other HIV protease inhibitors (eg, indinavir). The answer is F.

6. Amiodarone is an important antiarrhythmic drug and has a well-documented ability to inhibit the hepatic metabolism of many drugs. The answer is A.

7. Acetaminophen is normally eliminated by phase II conjugation reactions. The drug’s toxicity is caused by an oxidized reactive metabolite produced by phase I oxidizing P450 enzymes. Ethanol and certain other drugs induce P450 enzymes and thus reduce the hepatotoxic dose. Alcoholic cirrhosis reduces the hepatotoxic dose even more. The answer is B.

8. Ethanol is subject to metabolism in the stomach as well as in the liver. Independent of body weight and other factors, men have greater gastric ethanol metabolism and thus a lower ethanol bioavailability than women. The answer is B.

9. Verapamil is an inhibitor of P-glycoprotein drug transporters and has been used to enhance the cytotoxic actions of methotrexate in cancer chemotherapy. The answer is H.

10. While CYP2D6 is responsible for metabolizing approximately 25% of drugs, CYP3A4 is involved in almost 50% of such reactions. The answer is E.

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

• ❑ List the major phase I and phase II metabolic reactions. Know which P450 isoform is responsible for the greatest number of important 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.

• ❑ 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.