Species differences in the pharmacokinetics of KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide]: formation of hydrolyzed metabolite in human and animals.
Species differences in the pharmacokinetics of KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] were studied in in vivo and in vitro experiments. The exposure ratio of hydrolyzed metabolite (M2, primary metabolite in human plasma)/KW-7158 was higher than the ratio of thiophen-to-furan converted metabolite (M1)/KW-7158 in human subjects after oral administration, but the mouse, rat and dog studies gave opposite results. M2 was produced in the highest amount by the 9000g supernatant of small intestine, followed by that of liver and kidney in human subjects. After correction for protein contents, the results obtained suggested that the small intestine plays a major role in the metabolism to M2 for the first pass effect after oral administration of KW-7158. The formation of M2 was independent of the presence of NADPH and was inhibited by various esterase inhibitors. These observations suggested that the predominant enzymes or isozymes involved in the formation of M2 are esterases, which differ between humans and animals. Such differences may be one of the reasons for the species differences in the pharmacokinetics of KW-7158 between humans and animals.
Clinical Science Department, Development Division, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan. hiroshi.maeda@kyowa-kirin.co.jp
Hiroshi
H
Maeda
Hiroshi
H
Kodaira
Kazuhiro
K
Fujita
Hiroyuki
H
Kobayashi
Junko
J
Ushiki
Takeo
T
Nakanishi
Ikumi
I
Tamai
D000328:Adult; D000818:Animals; D001582:Benzothiepins / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007421:Intestine, Small / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D051381:Rats; D013045:Species Specificity
D001582:Benzothiepins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009249:NADP; C466985:KW 7158