Temocaprilat (RS5139) is an Angiotensin-converting Enzyme (ACE) inhibitor. Temocaprilat is effectively excreted in bile via cMOAT that is deficient in EHBR and that many of other ACE inhibitors have low affinity for cMOAT.

Biliary clearance of Temocaprilat after i.v. administration of [14C]temocapril x HCl (1.0 mg/kg) in EHBR was significantly lower than that in Sprague-Dawley rats (5.00 ml/min/kg for Sprague-Dawley rats vs. 0.25 ml/min/kg for EHBR). The uptake of Temocaprilat into canalicular membrane vesicles (CMVs) prepared from Sprague-Dawley rats was stimulated in the presence of ATP, whereas little stimulation was observed in CMVs from EHBR. The initial uptake rate of ATP-dependent transport of Temocaprilat showed saturation kinetics; we obtained an apparent V(max) value of 1.14 nmol/min/mg protein and a K(m) value 92.5 microM. ATP-dependent transport of Temocaprilat was competitively inhibited by 2,4-dinitrophenyl-S-glutathione, a typical substrate for cMOAT with an inhibition constant (K(i)) of 25.8 microM. The K(m) value for the uptake of 2,4-dinitrophenyl-S-glutathione into CMVs (K(m) = 29.6 microM) was consistent with this K(i) value. In addition, the ATP-dependent uptake of 2,4-dinitrophenyl-S-glutathione was inhibited by Temocaprilat in a concentration-dependent manner. Active forms of some ACE inhibitors (benazepril, cilazapril, delapril, enalapril and imidapril) did not affect the transport of Temocaprilat into CMVs even at concentrations as high as 200 microM[1].