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Induction of mixed function oxidase activity in man by rifapentine (MDL 473), a long-acting rifamycin derivative
Abstract:
The effects of rifapentine (MDL 473) administration on hepatic mixed function oxidase activity in man have been investigated in six healthy volunteers. Administration of rifapentine (600 mg 48 h-1) for 10 days resulted in a significant reduction in antipyrine half-life (from 13.2 +/- 1.0 h to 7.7 +/- 0.4 h) and a corresponding increase in its total body clearance (from 41.8 +/- 5.5 ml min-1 to 67.4 +/- 5.6 ml min-1). Twelve days after stopping rifapentine administration, these values had largely returned to base-line. 24-Hour excretion of 6 beta-hydroxycortisol was significantly increased, by approximately three-fold, following administration of rifapentine for 10 days. Again, 12 days after stopping drug administration, 6 beta-hydroxycortisol excretion had returned to pretreatment values. Clearance of antipyrine to its three oxidative metabolites was increased by rifapentine administration, although the increase for 3-hydroxymethylantipyrine was not significant. The greatest increase (+140%) was observed for norantipyrine. Twelve days after the last dose of rifapentine, all values had returned to control levels. It is concluded that, like rifampicin, rifapentine is a potent inducer of mixed function oxidase activity in man and that the possibility of clinically significant drug interactions should be anticipated in the therapeutic use of this compound.
Insights
Rifapentine significantly reduces antipyrine half-life and increases its clearance in healthy volunteers, indicating potent induction of drug-metabolizing enzymes. These effects are reversible after drug discontinuation, suggesting potential drug interactions.
Area of Science:
- Pharmacology
- Drug Metabolism
- Clinical Pharmacology
Background:
- Hepatic mixed function oxidase (MFO) systems are crucial for drug metabolism.
- Rifapentine is an antibiotic with potential MFO-modulating effects.
- Understanding rifapentine's impact on MFO activity is vital for predicting drug interactions.
Purpose of the Study:
- To investigate the effects of rifapentine administration on hepatic MFO activity in humans.
- To assess the impact of rifapentine on antipyrine pharmacokinetics and cortisol metabolism.
- To determine the reversibility of rifapentine's effects on MFO activity.
Main Methods:
- Six healthy volunteers received rifapentine (600 mg every 48 hours) for 10 days.
- Antipyrine half-life and total body clearance were measured.
- Excretion of 6 beta-hydroxycortisol and antipyrine metabolites was analyzed.
Main Results:
- Rifapentine significantly reduced antipyrine half-life and increased its clearance.
- A threefold increase in 24-hour 6 beta-hydroxycortisol excretion was observed.
- Clearance of antipyrine metabolites, particularly norantipyrine, increased significantly.
- All measured parameters returned to baseline 12 days after rifapentine cessation.
Conclusions:
- Rifapentine is a potent inducer of hepatic MFO activity in humans, similar to rifampicin.
- Clinically significant drug interactions should be anticipated with therapeutic rifapentine use.
- The MFO-inducing effects of rifapentine are reversible upon discontinuation.