Macitentan Does Not Interfere with Hepatic Bile Salt Transport

Abstract

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.

Pharmacokinetic and pharmacodynamic evaluation of macitentan, a novel endothelin receptor antagonist for the treatment of pulmonary arterial hypertension

“…However, further in vitro and in vivo studies, performed at clinically relevant concentrations, showed that macitentan is not a substrate of P-gp [59]. Hepatic uptake is mostly driven by passive diffusion and is not dependent on organic anion-transporting polypeptide (OATP) transport unlike other ERAs such as bosentan [73][74][75]. The limited drug interaction potential of macitentan was demonstrated in a number of drug--drug interaction studies and is summarized in Table 3.…”

Analysis of the Metabolic Pathway of Bosentan and of the Cytotoxicity of Bosentan Metabolites Based on a Quantitative Modeling of Metabolism and Transport in Sandwich-Cultured Human Hepatocytes

“…In the present in vitro metabolism studies, Ro 64-1056 was minimally metabolized in human liver microsomes, and therefore, the reactive metabolite formation is unlikely to be involved. Cholestasis is thought to be one of the hepatotoxic mechanisms of bosentan, and the canalicular efflux transporter BSEP and/or sinusoidal efflux transporters multidrug resistance-associated proteins 3 and 4 play roles in intracellular bile acid homeostasis (Fattinger et al, 2001;Zollner et al, 2007;Vanwijngaerden et al, 2011;Dawson et al, 2012;Treiber et al, 2014). In addition, disruption of mitochondrial function can lead to oxidative stress, apoptosis, and hepatocellular injury along with a reduction of intracellular ATP levels, and the dmd.aspetjournals.org combination of mitochondrial and BSEP inhibition should be more highly associated with the severity of human drug-induced liver injury (Aleo et al, 2014).…”

“…Since the hepatotoxic effects are reversible and dose-dependent (Fattinger et al, 2001;Rubin et al, 2002;Treiber et al, 2014), treatment discontinuation, dose reduction, or continued treatment coupled with monthly blood tests to monitor liver enzymes should be used in cases of liver enzyme abnormalities (Simonneau et al, 2014). Although the mechanisms underlying bosentan-induced liver injury are not yet fully understood, cholestatic liver injury is considered to be one of the hepatotoxic mechanisms of bosentan, and inhibition of hepatocanalicular bile salt export pump (BSEP) is at least partly involved (Fattinger et al, 2001;Dawson et al, 2012;Treiber et al, 2014). Bosentan potently inhibited both human BSEP-and rat Bsep-mediated taurocholate transport with similar IC 50 values (Dawson et al, 2012).…”

Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension

“…27 While passive diffusion is the driving force for macitentan uptake into the liver, low intrahepatic drug concentration limits BSEP transport proteins involved in hepatic bile salt homeostasis. 28 Therefore, in contrast to bosentan, macitentan does not interfere with BSEP. 28 The liver safety profile appears to give macitentan an additional advantage over bosentan in the treatment of PAH.…”

“…28 Therefore, in contrast to bosentan, macitentan does not interfere with BSEP. 28 The liver safety profile appears to give macitentan an additional advantage over bosentan in the treatment of PAH.…”