z-logo
open-access-imgOpen Access
Clinical drug-drug interactions of bosentan, a potent endothelial receptor antagonist, with various drugs: Physiological role of enzymes and transporters
Author(s) -
Nuggehally R. Srinivas
Publication year - 2016
Publication title -
general physiology and biophysics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.376
H-Index - 39
eISSN - 1338-4325
pISSN - 0231-5882
DOI - 10.4149/gpb_2015050
Subject(s) - bosentan , pharmacology , cyp3a4 , drug , endothelin receptor antagonist , pharmacokinetics , drug metabolism , drug interaction , cytochrome p450 , endothelin receptor , cyp2c19 , transporter , medicine , chemistry , metabolism , receptor , biochemistry , gene
Bosentan, an endothelin-1 (ET) receptor antagonist is an important drug for the effective management of patients with pulmonary arterial hypertension. Bosentan has a rather complicated pharmacokinetics in humans involving multiple physiological components that have a profound influence on its drug disposition. Bosentan is mainly metabolized by cytochrome P450 (CYP) 3A4 and 2C9 enzymes with the involvement of multiple transporters that control its hepatic uptake and biliary excretion. The involvement of phase 2 metabolism of bosentan is a key to have an enhanced biliary excretion of the drug-related products. While bosentan exhibits high protein binding restricting the drug from extensive distribution and significant urinary excretion, bosentan induces its own metabolism by an increased expression of CYP3A4 on repeated dosing. Due to the above properties, bosentan has the potential to display drug-drug interaction with the co-administered drugs, either being a perpetrator or a victim. The intent of this review is manifold: a) to summarize the physiological role of CYP enzymes and hepatic-biliary transporters; b) to discuss the mechanism(s) involved in the purported liver injury caused by bosentan; c) to tabulate the numerous clinical drug-drug interaction studies involving the physiological interplay with CYP and/or transporters; d) to provide some perspectives on dosing strategy of bosentan.

The content you want is available to Zendy users.

Already have an account? Click here to sign in.
Having issues? You can contact us here