ABSTRACT:The elimination process of the endothelin receptor antagonist bosentan (Tracleer) in humans is entirely dependent on metabolism mediated by two cytochrome P450 (P450) enzymes, i.e., CYP3A4 and CYP2C9. Most interactions with concomitantly administered drugs can be rationalized in terms of inhibition of these P450 enzymes. The increased bosentan concentrations observed in the presence of cyclosporin A, rifampicin, or sildenafil, however, are incompatible with this paradigm and prompted the search for alternative mechanisms governing these interactions. In the present article, we identify bosentan and its active plasma The phosphodiesterase-5 inhibitor sildenafil was also shown to interfere with OATP-mediated transport, however, at concentrations above those achieved in therapeutic use. Therefore, inhibition of bosentan hepatic uptake may represent an alternative/complementary mechanism to rationalize some of the pharmacokinetic interactions seen in therapeutic use. A similar picture has been drawn for drugs like pitavastatin and fexofenadine, drugs that are mainly excreted in unchanged form. Bosentan elimination, in contrast, is entirely dependent on metabolism. Therefore, the described interactions with rifampicin, cyclosporin A, and, to a lesser extent, sildenafil represent evidence that inhibition of hepatic uptake may become the rate-limiting step in the overall elimination process even for drugs whose elimination is entirely dependent on metabolism.Bosentan (Tracleer) is a dual endothelin receptor antagonist (Clozel et al., 1994;Neidhart et al., 1996) approved as the first oral treatment for pulmonary arterial hypertension (PAH) (Rubin et al., 2002). Its pharmacokinetic profile in humans is characterized by a low systemic plasma clearance of 17 l/h, a volume of distribution of about 30 l, and an oral bioavailability of about 50% (Dingemanse and van . At the maintenance dose of 125 mg b.i.d., bosentan trough concentrations decrease during the first days of treatment as a result of autoinduction of metabolizing enzymes, leading to an about 40% lower exposure at steady state. Bosentan is metabolized in the liver (Fig. 1), mediated to a similar extent by CYP2C9 and CYP3A4, followed by subsequent biliary excretion.Hydroxylation at the t-butyl group by CYP2C9 and CYP3A4 yields metabolite Ro 48-5033, a metabolite that retains pharmacological activity and is present in human plasma at levels of about 10% compared with parent bosentan. Ro 47-8634 is formed by oxidative demethylation of the guaiacol ether, catalyzed by CYP3A4, to the corresponding phenol, whereas metabolite Ro 64-1056 is formed as a minor product from both primary metabolites. Renal clearance of bosentan is negligible (Hopfgartner et al., 1996;Weber et al., 1999b). Based on preclinical data, the first-pass effect of bosentan is small. Bosentan is neither a substrate nor an inhibitor of the intestinal efflux pump MDR1 (P-glycoprotein, ABCB1) (Weber et al., 1999a;Treiber et al., 2004).Most of the pharmacokinetic drug-drug interactions observed w...

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.

Clin Pharmacol Ther advance online publication, January 24, 2007; doi: