Macitentan does not interfere with hepatic bile salt transport.

Area of Science:

• Pharmacology
• Hepatology
• Drug Metabolism

Background:

• Endothelin receptor antagonists like bosentan can cause liver injury by inhibiting the bile salt export pump (BSEP).
• Bosentan's liver accumulation, mediated by organic anion-transporting polypeptides (OATP), exacerbates hepatocellular damage.
• Pulmonary arterial hypertension (PAH) treatment requires agents with improved liver safety profiles.

Purpose of the Study:

• To investigate the mechanism behind macitentan's superior liver safety profile compared to other endothelin receptor antagonists.
• To elucidate the hepatic disposition and transporter interactions of macitentan.
• To confirm the reduced risk of drug-induced liver injury with macitentan in PAH patients.

Main Methods:

• In vitro experiments using drug transporter-expressing cell lines.
• In vivo studies in rats and dogs (acute and long-term).
• Clinical evaluation in healthy human volunteers and a Phase III PAH trial (SERAPHIN).

Main Results:

• Macitentan uptake into hepatocytes is primarily via passive diffusion, not OATP-mediated transport.
• Limited intrahepatic macitentan concentrations result in minimal interaction with BSEP and sodium taurocholate cotransporting polypeptide.
• Absence of plasma bile salt alterations and a favorable liver safety profile observed in clinical studies.

Conclusions:

• Macitentan's distinct pharmacokinetic profile minimizes hepatic accumulation and interaction with key bile salt transporters.
• This mechanism underlies macitentan's superior liver safety in the context of PAH treatment.
• Macitentan represents a safer therapeutic option for pulmonary arterial hypertension, reducing the risk of drug-induced liver injury.