Inhibitory and Inductive Effects of Rifampin on the Pharmacokinetics of Bosentan in Healthy Subjects

This study was conducted to investigate the effect of rifampin on the pharmacokinetics of bosentan. Healthy male subjects received bosentan 125 mg b.i.d. for 6.5 days in the presence or absence of rifampin 600 mg once a day. In vitro experiments were performed to investigate the effect of rifampin o...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2007-03, Vol.81 (3), p.414-419
Main Authors: Giersbergen, P L M, Treiber, A, Schneiter, R, Dietrich, H, Dingemanse, J
Format: Article
Language:English
Subjects:
Adult
Algorithms
Antibiotics, Antitubercular - pharmacology
Antihypertensive Agents - pharmacokinetics
Area Under Curve
Aryl Hydrocarbon Hydroxylases - biosynthesis
Biological and medical sciences
Bosentan
Chromatography, High Pressure Liquid
Cross-Over Studies
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - biosynthesis
Drug Interactions
Half-Life
Humans
Male
Mass Spectrometry
Medical sciences
Microsomes, Liver - drug effects
Microsomes, Liver - enzymology
Middle Aged
Pharmacology. Drug treatments
Rifampin - pharmacology
Sulfonamides - pharmacokinetics
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Summary:This study was conducted to investigate the effect of rifampin on the pharmacokinetics of bosentan. Healthy male subjects received bosentan 125 mg b.i.d. for 6.5 days in the presence or absence of rifampin 600 mg once a day. In vitro experiments were performed to investigate the effect of rifampin on the uptake of bosentan into Chinese hamster ovary cells expressing the human organic anion‐transporting polypeptide (OATP)1B1, −1B3, and −2B1. Following the first concomitant administration, there was a fivefold increase in bosentan trough concentrations. At steady state, concomitant rifampin significantly decreased exposure to bosentan by 58%. Rifampin potently inhibited the uptake of bosentan into cells expressing human OATP1B1 and −1B3. Rifampin decreased the exposure to bosentan consistent with its known cytochrome P450 enzyme‐inductive properties. The initial increase in bosentan concentrations can be explained by an inhibitory effect of rifampin on hepatic drug transporters. Clinical Pharmacology & Therapeutics (2007) 81, 414–419. doi:10.1038/sj.clpt.6100075; published online 24 January 2007.
ISSN:0009-9236
1532-6535
DOI:10.1038/sj.clpt.6100075