Metabolism and distribution of two highly potent and selective peptidomimetic inhibitors of matriptase.
Matriptase is a serine protease expressed by several types of cancer cells and it participates in tumour growth and progression through the activation of hepatocyte growth factor (HGF) and urokinase-type plasminogen activator (uPA). The metabolism of two potent and selective peptidomimetic inhibitors of matriptase (CJ-1737 and CJ-672) was examined in vitro with enzyme preparations (9000g supernatants, microsomes, and plasma) from dog, pig, rat, and human. It was found that both compounds displayed interesting species-dependent differences. Though CJ-1737 was not metabolized by microsomes, by 9000g supernatants from all species, or by human or rat plasma, canine and porcine plasma enzymes rapidly hydrolysed this compound. In contrast, CJ-672 was metabolized exclusively by enzymes from human liver (microsomes and 9000g supernatants) via a two-step metabolic pathway. Additionally, the distribution of both compounds was investigated in mice. The highest amounts were measured in the kidney and liver, followed by the spleen, lung, and heart. In contrast to CJ-1737, high concentrations of CJ-672 were detected in the colon, indicating an additional biliary excretion. In summary, this work clarifies both the metabolism and distribution of two new matriptase inhibitors and demonstrates important metabolic differences between human enzymes and those from commonly used laboratory animals.
Kotthaus
J
J
Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76, Kiel, Germany.
Steinmetzer
T
T
Kotthaus
J
J
Schade
D
D
van de Locht
A
A
Clement
B
B
D000578:Amidines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003106:Colon / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D012697:Serine Endopeptidases; D013045:Species Specificity; D013154:Spleen / Q000378:metabolism; D013552:Swine
D000578:Amidines; C548448:CJ 1737; C548449:CJ 672; D004791:Enzyme Inhibitors; D010649:Phenylalanine; D012697:Serine Endopeptidases; C485595:matriptase