E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability.
The metabolism of drugs can be induced or inhibited by concurrent therapy, and the importance of the effect varies from negligible to dramatic. Drug metabolism primarily occurs in the liver and the wall of the small intestine, but other sites include plasma, lung, and kidney. Induction of cytochrome P450 isozymes in the liver and small intestine can be caused by drugs such as barbiturates, bosentan, carbamazepine, efavirenz, nevirapine, phenytoin, primidone, rifampin, rifabutin, and St. John’s wort. Enzyme inducers can also increase the activity of phase II metabolism such as glucuronidation. Enzyme induction does not take place quickly; maximal effects usually occur after 7–14 days and require an equal or longer time to dissipate after the enzyme inducer is stopped. Inhibition of metabolism generally takes place more quickly than enzyme induction and may begin as soon as the tissue concentration of the inhibitor is sufficient to cause reduced enzyme activity. However, if the half-life of the affected (object) drug is long, it may take a week or more (3–4 half-lives) to reach a new steady-state serum concentration. Drugs that may inhibit the cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexiletine, miconazole, omeprazole, paroxetine, quinidine, ritonavir, sulfamethizole, sulfamethoxazole, verapamil, voriconazole, zafirlukast, and zileuton.
The renal excretion of active drug can also be affected by concurrent drug therapy. The renal excretion of drugs that are weak acids or weak bases may be influenced by other drugs that affect urinary pH. This is due to changes in ionization of the object drug, as described in Chapter 1 under Ionization of Weak Acids and Weak Bases; the Henderson-Hasselbalch Equation. For some drugs, active secretion into the renal tubules is an important elimination pathway. P-glycoprotein, organic anion transporters, and organic cation transporters are involved in active tubular secretion of some drugs, and inhibition of these transporters can inhibit renal elimination with attendant increase in serum drug concentrations. Many drugs are partially eliminated by P-glycoprotein, including digoxin, cyclosporine, dabigatran, colchicine, daunorubicin, and tacrolimus. The plasma concentration of these drugs can be increased by inhibitors of P-glycoprotein including amiodarone, clarithromycin, erythromycin, ketoconazole, ritonavir, and quinidine. To access over 200 brief reviews of specific drug interactions visit http://www.hanstenandhorn.com/news.htm.