For drugs administered orally, impaired gastrointestinal (GI) absorption is an important consideration. For example, aluminum ions in certain antacids or ferrous ions in oral iron supplements form insoluble chelates of tetracycline antibiotics, thereby preventing their absorption. The antifungal ketoconazole is a weak base that is only soluble at acid pH. Drugs that inhibit gastric acidity, such as the proton pump inhibitors and histamine H2 receptor antagonists, impair the dissolution and absorption of ketoconazole.
Many drug interactions involve the CYPs that perform phase 1 metabolism of a large number of drugs (see Chapter 3). Their expression can be induced by a plethora of drugs, including antibiotics (e.g., rifampin), anticonvulsants (e.g., phenobarbital, phenytoin, and carbamazepine), nonnu-cleoside reverse transcriptase inhibitors (e.g., efavirenz and nevirapine), and herbal supplements (e.g., St. John's wort). Although these drugs most potently induce CYP3A4, the expression of CYPs in the 1A, 2B, and 2C families also can be increased. Induction of these enzymes accelerates the metabolism of drugs that are their substrates, including cyclosporine, tacrolimus, warfarin, verapamil, methadone, dexamethasone, methylprednisolone, estrogen, and the HIV protease inhibitors. The decrease in oral bioavailability from increased first-pass metabolism in the liver results in loss of efficacy.
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