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.
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:
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.
TABLE 4–3A partial list of drugs that significantly induce P450-mediated drug metabolism in humans. ||Download (.pdf) 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, phenobarbital, rifampin, omeprazole ||Acetaminophen, clozapine, haloperidol, theophylline, tricyclic antidepressants, (R)-warfarin |
|2C9 ||Barbiturates, especially phenobarbital, phenytoin, primidone, rifampin ||Barbiturates, celecoxib, chloramphenicol, doxorubicin, 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, 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 |
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).
TABLE 4–4A partial list of drugs that significantly inhibit P450-mediated drug metabolism in humans. ||Download (.pdf) 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 |
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.