PHARMACOKINETIC DRUG INTERACTIONS
'----='--=
Clin. Pharmacokinet. 22 (I): 47-65, 1992 0312-5963/ 92/000 1-0047/$09.50/0 © Adis International Limited. All rights reserved. CPKl 1068
Pharmacokinetic Drug Interactions with Rifampicin K. Venkatesan Central JALMA Institute for Leprosy, Tajganj, Agra, India
Contents 47 48 48 49 54 55
56 56 58 59 59 60 60 60 6/
6/
62 62
Summary
Summary I. Effects of Rifampicin on Drugs 1.1 Oral Anticoagulants 1.2 Cardioactive Agents 1.3 Oral Contraceptives 1.4 Glucocorticoids 1.5 Hypoglycaemics 1.6 Narcotics and Analgesics I. 7 Cyclosporin 1.8 Antifungal Agents 1.9 Theophylline 1.10 Phenytoin 1.11 Vitamins and Hormones 1.12 Antituberculosis Drugs 1.13 Antileprosy Drugs 1.14 Others 2. Effects of Drugs on Rifampicin 3. Conclusions
Rifampicin, an antituberculosis drug, is usually administered for 4 to 12 months with other antituberculosis drugs or medications from other classes. A potential for drug interactions often exists because rifampicin is a potent inducer of hepatic drug metabolism, as evidenced by a proliferation of smooth endoplasmic reticulum and an increase in the cytochrome P450 content in the liver. The induction is a highly selective process and not every drug metabolised via oxidation is affected. Case reports and studies have demonstrated enhanced metabolism of several drugs; most of these interactions are clinically important. At the start of rifampicin treatment, and again at the end, clinicians must check the dosages of any accompanying medications with which rifampicin may potentially interact. Monitoring of clinical response and blood drug concentrations is essential to adjust the drug dosage during rifampicin therapy. Rifampicin also interacts with cholephils such as bilirubin and bromosulphthalein. Its pharmacokinetics are reported to be altered by ethambutol, p-aminosalicylic acid (through its excipient component), ketoconazole, cyclosporin, c1ofazimine, probenecid and phenobarbital through one or other of the following mechanisms - impaired absorption of rifampicin, competition between
48
Clin. Pharmacokinet. 22 (1) 1992
the drug and rifampicin for hepatic uptake and altered hepatic metabolism of rifampicin. Most interactions affecting rifampicin have been relatively minor or are not expected to alter its therapeutic efficacy.
Rifampicin (fig. 1) is used clinically in the treatment of tuberculosis, usually being administered for 4 to 12 months together with other antituberculosis agents or additional medications for an accompanying disease. It is a potent inducer of drug metabolism in humans and has been shown to produce a proliferation of smooth endoplasmic reticulum (Jezequel et al. 1971) and to increase the cytochrome P450 content of human liver (Bolt et al. 1975). There is a remarkable selectivity in the enzyme induction by rifampicin (Baciewicz & Self 1984) and not every drug metabolised by oxidation will be affected. Rifampicin also induces its own metabolism, thereby increasing its clearance; daily administration of the same dose results in a decreased halflife and a fall in blood concentrations due \~o dosedependent self-induction (Acocella 1978; Acocella et al. 1971; Furesz 1970). The maximal induction of rifampicin metabolism (and presumably that of the hepatic microsomal enzyme system in general) is probably attained after about 7 days' administration (Acocella et al. 1971; Immanual et al. 1985) [fig. 2]. This review reflects the current state of knowledge of pharmacokinetic drug interactions with
CH3
Rifampicin
Fig. 1. Chemical structure of rifampicin.
rifampicin and their therapeutic implications, and will discuss the management of situations that may arise due to such interactions. A summary of significant rifampicin-drug interactions is presented in table I.
1. Effects of Rifampicin on Drugs 1.1 Oral Anticoagulants One of the first reported rifampicin interactions was with oral anticoagulants. Several groups of workers noticed that patients on long term anticoagulants require an increase in the daily dose when rifampicin is coadministered. O'Reilly (1974), who measured prothrombin time and plasma warfarin concentrations in 10 male volunteers after single oral and intravenous doses of warfarin I.5 mg/kg (fig. 3) both before and during rifampicin treatment, observed a highly significant decrease in the mean areas under the prothrombin time-time curve and a corresponding decrease in plasma warfarin concentrations (table II). That there was no significant alteration in the absorption of the anticoagulant by rifampicin suggests an induction of warfarin metabolising enzymes. In a subsequent study (1975), the same author administered warfarin 7.5 to IOmg together with rifampicin 600mg daily to 8 volunteers for 21 days, and noted a highly significant decrease of hypoprothrombinaemic effect and plasma warfarin concentrations associated with increased excretion of warfarin metabolites in urine and stool for the last 10 days of the study. Romankiewicz and Ehrman (1975) have described cases in which simultaneous rifampicin 600 mg/day and warfarin resulted in the need for unusually high maintenance doses of warfarin (20 mg/day) in order to produce any therapeutic effect. Rifampicin withdrawal decreased the warfarin requirements by 50 to 60%. Similar observations were reported by Fox (1982).
Drug Interactions with Rifampi
'----='--=
Clin. Pharmacokinet. 22 (I): 47-65, 1992 0312-5963/ 92/000 1-0047/$09.50/0 © Adis International Limited. All rights reserved. CPKl 1068
Pharmacokinetic Drug Interactions with Rifampicin K. Venkatesan Central JALMA Institute for Leprosy, Tajganj, Agra, India
Contents 47 48 48 49 54 55
56 56 58 59 59 60 60 60 6/
6/
62 62
Summary
Summary I. Effects of Rifampicin on Drugs 1.1 Oral Anticoagulants 1.2 Cardioactive Agents 1.3 Oral Contraceptives 1.4 Glucocorticoids 1.5 Hypoglycaemics 1.6 Narcotics and Analgesics I. 7 Cyclosporin 1.8 Antifungal Agents 1.9 Theophylline 1.10 Phenytoin 1.11 Vitamins and Hormones 1.12 Antituberculosis Drugs 1.13 Antileprosy Drugs 1.14 Others 2. Effects of Drugs on Rifampicin 3. Conclusions
Rifampicin, an antituberculosis drug, is usually administered for 4 to 12 months with other antituberculosis drugs or medications from other classes. A potential for drug interactions often exists because rifampicin is a potent inducer of hepatic drug metabolism, as evidenced by a proliferation of smooth endoplasmic reticulum and an increase in the cytochrome P450 content in the liver. The induction is a highly selective process and not every drug metabolised via oxidation is affected. Case reports and studies have demonstrated enhanced metabolism of several drugs; most of these interactions are clinically important. At the start of rifampicin treatment, and again at the end, clinicians must check the dosages of any accompanying medications with which rifampicin may potentially interact. Monitoring of clinical response and blood drug concentrations is essential to adjust the drug dosage during rifampicin therapy. Rifampicin also interacts with cholephils such as bilirubin and bromosulphthalein. Its pharmacokinetics are reported to be altered by ethambutol, p-aminosalicylic acid (through its excipient component), ketoconazole, cyclosporin, c1ofazimine, probenecid and phenobarbital through one or other of the following mechanisms - impaired absorption of rifampicin, competition between
48
Clin. Pharmacokinet. 22 (1) 1992
the drug and rifampicin for hepatic uptake and altered hepatic metabolism of rifampicin. Most interactions affecting rifampicin have been relatively minor or are not expected to alter its therapeutic efficacy.
Rifampicin (fig. 1) is used clinically in the treatment of tuberculosis, usually being administered for 4 to 12 months together with other antituberculosis agents or additional medications for an accompanying disease. It is a potent inducer of drug metabolism in humans and has been shown to produce a proliferation of smooth endoplasmic reticulum (Jezequel et al. 1971) and to increase the cytochrome P450 content of human liver (Bolt et al. 1975). There is a remarkable selectivity in the enzyme induction by rifampicin (Baciewicz & Self 1984) and not every drug metabolised by oxidation will be affected. Rifampicin also induces its own metabolism, thereby increasing its clearance; daily administration of the same dose results in a decreased halflife and a fall in blood concentrations due \~o dosedependent self-induction (Acocella 1978; Acocella et al. 1971; Furesz 1970). The maximal induction of rifampicin metabolism (and presumably that of the hepatic microsomal enzyme system in general) is probably attained after about 7 days' administration (Acocella et al. 1971; Immanual et al. 1985) [fig. 2]. This review reflects the current state of knowledge of pharmacokinetic drug interactions with
CH3
Rifampicin
Fig. 1. Chemical structure of rifampicin.
rifampicin and their therapeutic implications, and will discuss the management of situations that may arise due to such interactions. A summary of significant rifampicin-drug interactions is presented in table I.
1. Effects of Rifampicin on Drugs 1.1 Oral Anticoagulants One of the first reported rifampicin interactions was with oral anticoagulants. Several groups of workers noticed that patients on long term anticoagulants require an increase in the daily dose when rifampicin is coadministered. O'Reilly (1974), who measured prothrombin time and plasma warfarin concentrations in 10 male volunteers after single oral and intravenous doses of warfarin I.5 mg/kg (fig. 3) both before and during rifampicin treatment, observed a highly significant decrease in the mean areas under the prothrombin time-time curve and a corresponding decrease in plasma warfarin concentrations (table II). That there was no significant alteration in the absorption of the anticoagulant by rifampicin suggests an induction of warfarin metabolising enzymes. In a subsequent study (1975), the same author administered warfarin 7.5 to IOmg together with rifampicin 600mg daily to 8 volunteers for 21 days, and noted a highly significant decrease of hypoprothrombinaemic effect and plasma warfarin concentrations associated with increased excretion of warfarin metabolites in urine and stool for the last 10 days of the study. Romankiewicz and Ehrman (1975) have described cases in which simultaneous rifampicin 600 mg/day and warfarin resulted in the need for unusually high maintenance doses of warfarin (20 mg/day) in order to produce any therapeutic effect. Rifampicin withdrawal decreased the warfarin requirements by 50 to 60%. Similar observations were reported by Fox (1982).
Drug Interactions with Rifampi
