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Temocaprilat, a novel angiotensin-converting enzyme inhibitor, is excreted in bile via an ATP-dependent active transporter (cMOAT) that is deficient in Eisai hyperbilirubinemic mutant rats (EHBR). 1997

H Ishizuka, and K Konno, and H Naganuma, and K Sasahara, and Y Kawahara, and K Niinuma, and H Suzuki, and Y Sugiyama
Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.

Temocapril x HCl (alpha-((2S,6R)-6-[(1S)-1-ethoxy-carbonyl-3-phenyl-propyl]amino-5-oxo-2- (2-thienyl)perhydro-1,4-thiazepin-4-yl)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 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. 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.

UI MeSH Term Description Entries
D011922 Rats, Mutant Strains Rats bearing mutant genes which are phenotypically expressed in the animals. Mutant Strains Rat,Mutant Strains Rats,Rat, Mutant Strains,Strains Rat, Mutant,Strains Rats, Mutant
D002352 Carrier Proteins Proteins that bind or transport specific substances in the blood, within the cell, or across cell membranes. Binding Proteins,Carrier Protein,Transport Protein,Transport Proteins,Binding Protein,Protein, Carrier,Proteins, Carrier
D006933 Hyperbilirubinemia, Hereditary Inborn errors of bilirubin metabolism resulting in excessive amounts of bilirubin in the circulating blood, either because of increased bilirubin production or because of delayed clearance of bilirubin from the blood. Rotor Syndrome,Hyperbilirubinemia, Rotor Type,Hereditary Hyperbilirubinemia,Hereditary Hyperbilirubinemias,Hyperbilirubinemias, Hereditary,Rotor Type Hyperbilirubinemia,Syndrome, Rotor
D000255 Adenosine Triphosphate An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D000806 Angiotensin-Converting Enzyme Inhibitors A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. ACE Inhibitor,ACE Inhibitors,Angiotensin Converting Enzyme Inhibitor,Angiotensin I-Converting Enzyme Inhibitor,Angiotensin-Converting Enzyme Inhibitor,Kininase II Inhibitor,Kininase II Inhibitors,Angiotensin I-Converting Enzyme Inhibitors,Angiotensin-Converting Enzyme Antagonists,Antagonists, Angiotensin-Converting Enzyme,Antagonists, Kininase II,Inhibitors, ACE,Inhibitors, Angiotensin-Converting Enzyme,Inhibitors, Kininase II,Kininase II Antagonists,Angiotensin Converting Enzyme Antagonists,Angiotensin Converting Enzyme Inhibitors,Angiotensin I Converting Enzyme Inhibitor,Angiotensin I Converting Enzyme Inhibitors,Antagonists, Angiotensin Converting Enzyme,Enzyme Antagonists, Angiotensin-Converting,Enzyme Inhibitor, Angiotensin-Converting,Enzyme Inhibitors, Angiotensin-Converting,II Inhibitor, Kininase,Inhibitor, ACE,Inhibitor, Angiotensin-Converting Enzyme,Inhibitor, Kininase II,Inhibitors, Angiotensin Converting Enzyme
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001646 Bile An emulsifying agent produced in the LIVER and secreted into the DUODENUM. Its composition includes BILE ACIDS AND SALTS; CHOLESTEROL; and ELECTROLYTES. It aids DIGESTION of fats in the duodenum. Biliary Sludge,Sludge, Biliary
D001648 Bile Canaliculi Minute intercellular channels that occur between liver cells and carry bile towards interlobar bile ducts. Also called bile capillaries. Bile Canaliculus,Canaliculi, Bile,Canaliculus, Bile
D013045 Species Specificity The restriction of a characteristic behavior, anatomical structure or physical system, such as immune response; metabolic response, or gene or gene variant to the members of one species. It refers to that property which differentiates one species from another but it is also used for phylogenetic levels higher or lower than the species. Species Specificities,Specificities, Species,Specificity, Species
D013841 Thiazepines Compounds that are derivatives of THIEPINS, with a nitrogen replacing a carbon in the seven-membered heterocyclic compound. Thiazepine

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