The consequences of administering strong enzyme inducers to human subjects (e.g. rifampicin and phenytoin) have been well documented, and several are described here to highlight the clinical issues associated with potential reductions in clinical efficacy. These include oral contraceptives (risk of conception), calcium channel blockers (loss of blood pressure control), anti-HIV drugs (lack of suppression of HIV replication), and several anti-cancer agents (reduced anti-tumor activity?).
Oral contraceptive - In humans, the metabolism of ethinylestradiol (6), the usual estrogenic component of the oral contraceptive pill, involves sulfation (sulfotransferases) to form the EE-3-O-sulfate, and glucuronidation (UGT1A1) to form EE-3-O-glucuronide. Alternatively, ethinylestradiol is hydroxylated at C2, C4, C6, or C16 to the corresponding hydroxy-derivatives, which subsequently are methylated to form methoxy derivatives and conjugated to form the corresponding methoxy sulfate or methoxy glucuronide. Following oral administration of ethinylestradiol to humans, AUC values for parent compound vary -10-fold among different individuals and the oral bioavailability ranges from -20-65%. The low bioavailability of ethinylestradiol is not due to poor absorption, but to first pass metabolism. The contribution of the gut and liver to fHjethinylestradiol first pass metabolism has been studied in humans. The extraction of ethinylestradiol by gut (Ea) and liver (Eh) has been estimated to be -44% and 25% and the mean bioavailability is -45% (89, 90).
In another study, premenopausal women were treated with 35 ng ethinylestradiol/1 mg norethindrone (91). Subjects received 14 days of rifampicin (600 mg per day) from days 7-21 of their menstrual cycle. Rifampicin significantly decreased the mean area of the concentration of ethinylestradiol (66%) and norethindrone (51%). The mean Cma* decreased by 43% from base line for ethinylestradiol and the tic decreased by 48%. The mechanism of this interaction was attributed to CYP3A4 induction. Interestingly, troglitazone administration (600 mg daily, 22 days) reduced AUC values for ethinylestradiol on day 21 by -30%, and it was reported that troglitazone may enhance the conjugation pathways of ethinylestradiol metabolism (72). This is one of the few reports citing the up-regulation of Phase 2 pathways as a mechanism by which ethinylestradiol interacts with other drugs.
Calcium-channel blockers - The interaction between rifampicin and the dihydropyridine calcium-channel blockers resulted in loss of efficacy with potential adverse consequences of controlling blood pressure in the elderly. Rifampicin was given to treat tuberculosis in four elderly hypertensive patients whose blood pressure was well-controlled by one or more dihydropyridine calcium-channel blockers (nisoldipine, nifedipine, or barnidipine and manidipine). Shortly after the start of antituberculosis therapy, their blood pressures rose. Either much greater doses of dihydropyridines or additional antihypertensive agents had to be given to keep blood pressure under control. After withdrawal of rifampicin, blood pressure fell in all patients and the doses of the antihypertensive agents had to be reduced. These findings indicated that rifampicin could lessen the antihypertensive effects of dihydropyridine calcium-channel blockers (92).
Anti-HIV drugs - Co-administration of rifampicin (600 mg) with nelfinavir (750 mg, t.i.d.), a CYP3A substrate, resulted in a 76% reduction in Cmax and an 82% reduction in
AUC. Since the degree and duration of suppression of HIV replication is significantly correlated with plasma concentrations, this co-medication has been contraindicated because of the potential for drug interactions which could result in clinically significant adverse events (93).
Irinotecan (CPT-11. 7) - is a water-soluble topoisomerase I inhibitor used for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following 5-fluorouracil-based therapy (94). Irinotecan is metabolized by carboxylesterase enzymes to form an active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), which Is 100 to 1000-fold more potent than parent compound. Irinotecan can also undergo CYP3A4-mediated metabolism to form a
pharmacologically inactive metabolite, 7-ethyl-10-[4-N-[(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC), formed following a-N-oxidatlon of the outer piperidine, and NPC, a primary amine metabolite formed by oxidative cleavage of both a-carbons of the outer piperidine. Co-administration of irinotecan with strong inducers of the CYP3A4 pathway have the potential to reduce its efficacy by increasing the proportion of drug undergoing oxidative metabolism to APC and NPC. The pharmacokinetic profile of irinotecan and its major metabolites with and without concomitant phenytoin administration in an individual patient has been reported (95). These studies revealed that phenytoin administration resulted in a marked decrease in the systemic exposure to irinotecan and SN-38 and an increase In the exposure to APC. The area under the curve of irinotecan and SN-38 decreased by 63% and 60%, respectively; the area under the curve of APC increased by approximately 16%, indicating that phenytoin administration had induced CYP3A4. These authors concluded that further detailed pharmacokinetic studies of irinotecan in patients receiving concomitant therapy with enzyme-inducing anticonvulsants (e.g. phenytoin, dexamethasone) are required so that rational dosing recommendations can be provided for this patient population.
Tamoxifen (8) and toremifene - Rifampin (600mg once daily for 5 day) reduced the area under the plasma concentration-time curve (AUC) of tamoxifen (80 mg, given on day 6) by 86%, peak plasma concentration (Cmax) by 55%, and elimination half-life (tic) by 44%. The AUC of toremifene (120 mg given on day 6) was reduced by 87%, Cmax by 55%, and ti« by 44% with rifampin. Rifampin therefore markedly reduced the plasma concentrations of tamoxifen and toremifene by inducing their CYP3A4-mediated metabolism. It was concluded that concomitant use of rifampin or other strong inducers of CYP3A4 with tamoxifen and toremifene may reduce the efficacy of these antiestrogens (96).
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