Effect of rifampicin on metoprolol and antipyrine kinetics.

The effect of rifampicin on the blood concentration-time curve of propranolol at steady-state following oral administration of 120 mg every 8 h was investigated in six normal, young, male subjects. After an initial 2 week dosing period, all individuals additionally received 600 mg rifampicin daily for 3 weeks followed by a 4 week period during which again only the propranolol was given. In four of the subjects the effects of 900 and 1200 mg rifampicin daily was also studied. Changes in disposition were assessed by estimation of propranolol's oral clearance and elimination half-life during the dosage interval. Rifampicin (600 mg/day) caused a large increase in propranolol's oral clearance (35.7 + 16.3 vs 96.1 + 26.9 ml min-m kg-', mean + s.d.), but neither the elimination half-life nor extent of plasma binding were affected. Increasing the daily dosage to 900 and 1200 mg did not cause any additional changes in oral clearance. Four weeks after discontinuing rifampicin, propranolol's oral clearance had essentially returned to its pre-induction level. The oral clearance of propranolol was significantly smaller (89.5 + 14.4%) during the dosage interval immediately after administration of the last rifampicin dose than the value measured 24 h later. The findings are consistent with rifampicin causing induction of the drug metabolizing enzymes responsible for propranolol's biotransformation. The marked reduction in the steady-state propranolol blood concentration that results from chronic rifampicin administration would be expected to result in a significant change in clinical effectiveness of the ,/-adrenoceptor blocker when the two drugs are used concurrently.

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Induction of propranolol metabolism by rifampicin.

Herman¹,

Nakamura²,

Wilkinson³

et al. 1983

“…Administration of rifampicin to volunteers for 13 days reduced the AUC for metoprolol and also increased antipyrine clearance (Bennett et al, 1982). It was concluded that the changes in metoprolol kinetics were due to induction of microsomal enzymes.…”

Section: Ikylation Side-chain Oxidationmentioning

confidence: 98%

Prediction of metabolic drug interactions involving beta‐adrenoceptor blocking drugs.

Park¹

1984

1 There is evidence, from human and animal studies, that drug-metabolising enzymes exist in multiple forms, the individual enzymes having selective, but not specific, substrate requirements. Consequently drug interactions may arise when two drugs bind to the same enzyme. The degree of enzyme inhibition will be partly dependent on the relative affinities of the drugs for the enzyme and on their rates of turnover. The decrease in drug clearance produced by enzyme inhibition is dependent on the fraction of the drug normally metabolised by the inhibited pathway(s). 2 Cimetidine, a P-450 enzyme inhibitor, increases the systemic bioavailability of propranolol and labetalol, which undergo extensive metabolism, but does not affect the clearance of atenolol, which is excreted largely unchanged. In this situation, both the extent and type of biotransformation are important. Thus, cimetidine has no effect on the clearance of penbutolol, even though the drug is eliminated almost entirely by biotransformation. The major metabolite is penbutolol glucuronide, and it has been shown recently that cimetidine does not inhibit glucuronylation. 3 f3-adrenoceptor blockers also act as enzyme inhibitors themselves. For example, antipyrine clearance is decreased by propranolol and to a lesser extent by metoprolol, whereas atenolol has no effect. It has been suggested, therefore, that there is a relationship between the lipid-solubility of 18-adrenoceptor blockers and their ability to inhibit drug metabolism.4 The clearance of lipophilic ,3-adrenoceptor blockers is dependent on hepatic enzyme activity, and is therefore sensitive to enzyme induction. For drugs with high hepatic clearance and subsequent high presystemic elimination, a moderate increase in the extraction ratio will produce a marked decrease in systemic bioavailability. Thus pentobarbitone enzyme induction increased the hepatic extraction of alprenolol by 29% and decreased the AUC by 78%. 5 The impact of changes in the activity of the drug-metabolising enzymes on drug clearance is dependent upon the extent and type of biotransformation(s) that the interacting drugs undergo. A better understanding of such drug interactions will be obtained by measuring metabolite formation rather than clearance of parent drug.

“…Over recent years, studies of antipyrine kinetics in enzyme-induced subjects have used either oral (Roberts et al, 1976;Perucca et al, 1984;Bennett et al, 1982;Pessayre et al, 1978) or intravenous (Perucca et al, 1980) antipyrine administration. It has not been directly demonstrated whether the antipyrine bioavailability was complete in the oral studies or whether significant presystemic elimination occurred in the gut.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of antipyrine in epileptic patients.

Rimmer¹,

Routledge²,

Tsanaclis³

et al. 1986

The pharmacokinetics of antipyrine were examined after oral and intravenous administration to 20 epileptic subjects receiving antiepileptic drug therapy. Bioavailability was essentially complete (mean bioavailability 101.2% + 14.4 (s.d.)) indicating that even in enzyme induced subjects, antipyrine behaves as a restrictively eliminated compound with negligible presystemic elimination in the gut or liver. Of the generally used measures of enzyme induction (oral clearance, oral half-life and intravenous half-life) oral clearance was the most closely related to the intravenous clearance of antipyrine (r = 0.919, P < 0.001). Oral antipyrine administration is an alternative to intravenous administration in epileptic subjects who are enzyme-induced.