Enzyme-inducing drugs include various sedative-hypnotics, antipsychotics, anticonvulsants, the antitubercular drug rifampin, and insecticides (Table 4–5). Patients who routinely ingest barbiturates, other sedative-hypnotics, or certain antipsychotic drugs may require considerably higher doses of warfarin to maintain a therapeutic effect. On the other hand, discontinuance of the sedative inducer may result in reduced metabolism of the anticoagulant and bleeding—a toxic effect of the ensuing enhanced plasma levels of the anticoagulant. Similar interactions have been observed in individuals receiving various combinations of drug regimens such as rifampin, antipsychotics, or sedatives with contraceptive agents, sedatives with anticonvulsant drugs, and even alcohol with hypoglycemic drugs (tolbutamide). One inducer of note is St. John’s wort, a popular over-the-counter herbal medicine ingested as treatment for mild to severe depression. Because of its marked induction of hepatic CYP3A4 and, to a lesser extent, CYP2C9 and CYP2C19, St. John’s wort has been linked to a large number of DDIs. Most of such DDIs stem from P450 induction by St. John’s wort and entail accelerated P450-dependent metabolism of the co-ingested drug (eg, alprazolam, contraceptive estrogens, warfarin, lovastatin, delavirdine, ritonavir). In contrast, St. John’s wort-mediated CYP2C19 induction may enhance the activation of the antiplatelet prodrug clopidogrel by accelerating its conversion to the active metabolite. Finally, some St. John’s wort-elicited DDIs may entail decreased P450-dependent metabolism due to competitive inhibition and consequently increased plasma levels and clinical effect (eg, meperidine, hydrocodone, morphine, oxycodone). Other DDIs entail synergistic increases in serotonin levels (due to monoamine oxidase inhibition) and correspondingly increased serotonergic tone and adverse effects (eg, paroxetine, sertraline, fluoxetine, fenfluramine).
It must also be noted that an inducer may enhance not only the metabolism of other drugs but also its own metabolism.
TABLE 4–5 Partial list of drugs that enhance drug TABLE 4–6 Partial list of drugs that inhibit drug metabolism in humans. metabolism in humans.
1Secobarbital is an exception. See Table 4–6 and text.
2With chronic (repeated) administration; acutely, ritonavir is a potent CYP3A4 inhibitor/inactivator.
3For a more comprehensive list of drugs whose metabolism is enhanced by St. John’s wort, see Rahimi and Abdollahi, 2012; Russo et al, 2014; and Tsai et al, 2012.
Thus, continued use of some drugs may result in a pharmacokinetic type of tolerance—progressively reduced therapeutic effectiveness due to enhancement of their own metabolism.