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.
Subject(s)
ATP-Binding Cassette Transporters/drug effects , Bile Acids and Salts/blood , Liver/metabolism , Organic Anion Transporters, Sodium-Dependent/drug effects , Pyrimidines/pharmacokinetics , Pyrimidines/toxicity , Sulfonamides/pharmacokinetics , Sulfonamides/toxicity , Symporters/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 11 , Animals , Bosentan , Cell Line , Cricetinae , Dogs , Dose-Response Relationship, Drug , Endothelin Receptor Antagonists , Hepatocytes , Humans , Male , Organic Anion Transporters/drug effects , Pyrimidines/adverse effects , Rats , Sulfonamides/adverse effectsABSTRACT
OBJECTIVES: Gadoxetic acid [gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA); Primovist] is a liver specific contrast agent for magnetic resonance imaging. For risk assessment of the single diagnostic use the toxicity of this compound was assessed. MATERIALS AND METHODS: Studies into acute, repeated-dose, reproductive and developmental toxicity, and local tolerance, contact sensitizing, and genotoxic potential were performed. RESULTS: Lethality was observed after a single intravenous administration at doses 2 orders of magnitude higher than the clinical dose. The no observed adverse effect levels after repeated administration markedly exceeds the single diagnostic dose in humans and no unexpected organ toxicity was observed. No indications of reproductive and developmental toxicity, potential contact allergenic, and genotoxic effects were observed. Gd-EOB-DTPA was well tolerated after intravenous administration. CONCLUSIONS: Gd-EOB-DTPA was well tolerated with high safety margins between the single diagnostic dose and the doses showing adverse effects in animal studies.
