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Vol. 280, Issue 3, 1304-1311, 1997
Analytical and Metabolic Research Laboratories (H.I., K.K., H.N.,
K.S., Y.K.), Sankyo Co., Ltd., Tokyo, Japan and the
Faculty of
Pharmaceutical Sciences (K.N., H.S., Y.S.), The University of Tokyo,
Tokyo, Japan
Temocapril · HCl
(
-{(2S,6R)-6-[(1S)-1-ethoxy-carbonyl-3-phenyl-propyl]amino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4yl}acetic acid hydrochloride) is a novel prodrug of an angiotensin-converting enzyme (ACE) inhibitor. Unlike many other ACE inhibitors, its pharmacologically active metabolite,temocaprilat, is excreted predominantly in bile. To investigate the mechanism for the biliary excretion of temocaprilat, we performed in vivo and in
vitro experiments using mutant Eisai hyperbilirubinemic rats EHBR)
whose canalicular multispecific organic anion transporter (cMOAT) is
hereditarily defective. Biliary clearance of temocaprilat after i.v.
administration of [14C]temocapril · 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
Vmax value of 1.14 nmol/min/mg protein and a
Km value 92.5 µM. ATP-dependent transport of
temocaprilat was competitively inhibited by
2,4-dinitrophenyl-S-glutathione, a typical substrate for
cMOAT with an inhibition constant (Ki) of 25.8 µM. The Km value for the uptake of
2,4-dinitrophenyl-S-glutathione into CMVs (Km = 29.6 µM) was consistent with this
Ki 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 µM. These data suggest that
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.
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