Characteristics of gastrointestinal absorption of DX-9065a, a new synthetic anticoagulant.
DX-9065a, a newly synthesized anticoagulant that selectively inhibits factor Xa, is a zwitterion and has characteristics of high water solubility and low lipophilicity. We predicted the fraction absorbed (Fa) of DX-9065a to be approximately 15-35% in humans, based on the boundary layer theory using the intestinal perfusion method in rats. However, human oral bioavailability was 2-3% in clinical trials, and the result of actual human bioavailability was lower than that of the predicted Fa. Thus, in this report, the reason for low oral bioavailability of DX-9065a was examined by in vitro and in vivo experiments. The factors affecting oral bioavailability of DX-9065a were not the hepatic first-pass effect, degradation of the drug in intestinal fluid, nor the interaction of the drug with the intestinal mucin. Furthermore, no effect of P-gp efflux was observed. Oral absorption of the drug in rats with bile duct ligation was significantly higher than that in normal rats with bioavailability of 17 and 3%, respectively. It was confirmed that bile acids inhibited DX-9065a absorption because DX-9065a interacted with bile acids to form insoluble complexes. The results suggest that the complex formation of DX-9065a with bile acids in the intestinal tract is an important factor affecting absorption of DX-9065a.
Fujii
Yoshimine
Y
Drug Metabolism & Physicochemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. fujiic2b@daiichipharm.co.jp
Takahashi
Masayuki
M
Morita
Hiromi
H
Kikuchi
Hiroshi
H
Aramaki
Yukihiko
Y
Amidon
Gordon L
GL
D000465:Algorithms; D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics*; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000378:metabolism / Q000502:physiology; D001682:Biological Availability; D001826:Body Fluids / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003956:Dialysis; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D008026:Ligation; D008297:Male; D008567:Membranes, Artificial; D015233:Models, Statistical; D009281:Naphthalenes / Q000493:pharmacokinetics*; D010477:Perfusion; D011422:Propionates / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D001647:Bile Acids and Salts; D008567:Membranes, Artificial; D009281:Naphthalenes; D011422:Propionates