Macitentan is a new non-selective endothelin-1 receptor antagonist under 
development for the treatment of pulmonary arterial hypertension. Information on 
the potential for macitentan to influence the pharmacokinetics of concomitantly 
administered drugs by inhibition or induction of drug metabolising enzymes or 
drug transporters is sparse. We therefore studied the potential of macitentan to 
inhibit and induce critical targets of drug metabolism and drug distribution 
(transporters) in vitro. Induction was quantified at the mRNA level by real-time 
RT-PCR in LS180 cells and revealed that macitentan significantly induced mRNA 
expression of cytochrome P450 3A4 (CYP3A4), P-glycoprotein (P-gp, ABCB1), solute 
carrier of organic anions 1B1 (SLCO1B1), and 
uridinediphosphate-glucuronosyltransferase 1A3 (UGT1A9). By means of a reporter 
gene assay our study establishes macitentan as a potent activator of pregnane X 
receptor (PXR). Inhibition of drug transporters was evaluated by using 
transporter over-expressing cell lines and fluorescent specific substrates of 
the respective transporters and revealed that macitentan is an inhibitor of 
P-gp, breast cancer resistance protein (BCRP), SLCO1B1, and SLCO1B3. Using 
commercial kits macitentan was demonstrated to be a moderate inhibitor of CYP3A4 
and CYP2C19. In conclusion our data provide a comprehensive analysis of the 
interaction profile of macitentan with drug metabolising and transporting 
enzymes in vitro. Although macitentan has a similar or higher potency for 
induction and inhibition of drug metabolising enzymes and transporters than 
bosentan, its low plasma concentrations and minimal accumulation in the liver 
suggest that it will be markedly less prone to drug-drug interactions than 
bosentan.