Macitentan does not interfere with hepatic bile salt transport.
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.
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland alexander.treiber@actelion.com.
Alexander
A
Treiber
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Päivi
P
Äänismaa
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Ruben
R
de Kanter
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Stephane
S
Delahaye
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Marianne
M
Treher
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Patrick
P
Hess
Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., P.A., R.d.K., S.D.), Toxicology (M.T.), Pharmacology (P.H.), and Clinical Pharmacology (P.S.), Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Patricia
P
Sidharta
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects*; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood*; D000077300:Bosentan; D002460:Cell Line; D006224:Cricetinae; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D022781:Hepatocytes; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000187:drug effects; D029363:Organic Anion Transporters, Sodium-Dependent / Q000187:drug effects*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000633:toxicity*; D027981:Symporters / Q000187:drug effects*
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D065128:Endothelin Receptor Antagonists; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D011743:Pyrimidines; D013449:Sulfonamides; D027981:Symporters; C071908:sodium-bile acid cotransporter; C572762:aprocitentan; D000077300:Bosentan; C533860:macitentan