PT  - JOURNAL ARTICLE
AU  - Treiber, Alexander
AU  - Äänismaa, Päivi
AU  - de Kanter, Ruben
AU  - Delahaye, Stephane
AU  - Treher, Marianne
AU  - Hess, Patrick
AU  - Sidharta, Patricia
TI  - Macitentan Does Not Interfere with Hepatic Bile Salt Transport
AID  - 10.1124/jpet.114.214106
DP  - 2014 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 130--143
VI  - 350
IP  - 1
4099  - http://jpet.aspetjournals.org/content/350/1/130.short
4100  - http://jpet.aspetjournals.org/content/350/1/130.full
SO  - J Pharmacol Exp Ther2014 Jul 01; 350
AB  - Treatment of pulmonary arterial hypertension with the endothelin receptor antagonist bosentan has been associated with transient increases in liver transaminases. Mechanistically, bosentan inhibits the bile salt export pump (BSEP) leading to an intrahepatic accumulation of cytotoxic bile salts, which eventually results in hepatocellular damage. BSEP inhibition by bosentan is amplified by its accumulation in the liver as bosentan is a substrate of organic anion-transporting polypeptide (OATP) transport proteins. The novel endothelin receptor antagonist macitentan shows a superior liver safety profile. Introduction of the less acidic sulfamide moiety and increased lipophilicity yield a hepatic disposition profile different from other endothelin receptor antagonists. Passive diffusion rather than OATP-mediated uptake is the driving force for macitentan uptake into the liver. Interaction with the sodium taurocholate cotransporting polypeptide and BSEP transport proteins involved in hepatic bile salt homeostasis is therefore limited due to the low intrahepatic drug concentrations. Evidence for this conclusion is provided by in vitro experiments in drug transporter-expressing cell lines, acute and long-term studies in rats and dogs, absence of plasma bile salt changes in healthy human volunteers after multiple dosing, and finally the liver safety profile of macitentan in the completed phase III morbidity/mortality SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial.