AIMSThe aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion-transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of CYP2C9 and SLCO1B1 (encoding for OATP1B1) genotypes and their combination. METHODSWe assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug. Sixteen healthy volunteers received therapeutic doses of bosentan (125 mg twice daily) for 14 days and clarithromycin (500 mg twice daily) concomitantly for the last 4 days, and bosentan pharmacokinetics was assessed on days 1, 10 and 14. RESULTSClarithromycin significantly increased bosentan area under the plasma concentration-time curve of the dosing interval 3.7-fold and peak concentration 3.8-fold in all participants irrespective of the genotype. Clarithromycin also reduced CYP3A activity (midazolam clearance) in all participants; however, these changes were not correlated to the changes of bosentan clearance. CONCLUSIONSClarithromycin substantially increases the exposure to bosentan, suggesting that dose reductions may be necessary. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Exposure to the endothelin antagonist bosentan depends on the activity of the cytochrome P450 isozymes CYP3A4 and polymorphic CYP2C9 and the activity of organic anion-transporting polypeptides (OATP) 1B1 and 1B3.• Clarithromycin is a potent inhibitor of CYP3A4 and OATP1B1, suggesting that concomitant therapy will result in a major increase in bosentan exposure. WHAT THIS STUDY ADDS• Our study shows that clarithromycin substantially increases the exposure to bosentan and the active hydroxy-metabolite, suggesting that dose reductions may be necessary.• The CYP2C9 and OATP1B1 polymorphisms had no influence on bosentan pharmacokinetics.

Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.

To evaluate the impact of CYP2C19 polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 CYP2C19 extensive, four poor and six ultrarapid metabolizers) received therapeutic doses of ambrisentan (5 mg qd po) for 20 days and concomitantly SJW (300 mg tid po) for the last 10 days. To quantify changes of CYP3A4 activity, midazolam (3 mg po) as a probe drug was used. Ambrisentan pharmacokinetics was assessed on days 1, 10 and 20, and midazolam pharmacokinetics before and on days 1, 10, 17 and 20. At steady state, ambrisentan exposure was similar in extensive and ultrarapid metabolizers but 43% larger in poor metabolizers (p < 0.01). In all volunteers, SJW reduced ambrisentan exposure and the relative change (17-26%) was similar in all genotype groups. The extent of this interaction did not correlate with the changes in CYP3A activity (midazolam clearance) (r s = 0.23, p = 0.34). Ambrisentan had no effect on midazolam pharmacokinetics. In conclusion, SJW significantly reduced exposure with ambrisentan irrespective of the CYP2C19 genotype. The extent of this interaction was small and thus likely without clinical relevance.Ambrisentan is an ET A -selective endothelin-1 receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), which is a devastating disease characterized by elevated pulmonary arterial pressure, right ventricular failure and ultimately death. Ambrisentan improved the quality of life and exercise capacity as determined by the 6-min. walking distance, decreased dyspnoea and delayed the time to clinical worsening in patients with PAH. Also haemodynamic (e.g. pulmonary vascular resistance) and hormonal (e.g. N-terminal-pro-hormone-brain natriuretic peptide) endpoints were improved [1,2].Common side effects of ERA include headache, hepatotoxicity, peripheral oedema and nasal congestion, which dose dependently increase in frequency; for example, doubling the dose doubled ambrisentan-associated nasal congestion [1]. Higher doses of ambrisentan also lead to more pronounced beneficial effects [1], suggesting that effects and side effects of ambrisentan are dose dependent, and substantial changes in exposure are likely of clinical relevance.Clearance of ambrisentan is mainly determined by the uridine diphosphate glucuronosyltransferase (UGT) isozymes UGT1A9, UGT2B7 and UGT1A3. A minor part of the drug (20%) undergoes phase I oxidative metabolism mainly by cytochrome P450 (CYP) 3A4 and to a lesser extent by the polymorphic CYPs 3A5 and 2C19 to form the pharmacologically inactive 4-hydroxymethyl ambrisentan [3]. Organic anion-transporting polypeptides (OATP) partly mediate the hepatic uptake of ambrisentan, while efflux transporters do not appear to be involved in its kinetics [4,5].More than 50% of PAH patients show depressive symptoms [6] with every fifth patient being in need of pharmacological therapy [7]. Self-medication of St John's wort (Hypericum perforatum, SJW) is often unrecognized [8] and may de...

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