Characteristics of Gastrointestinal Absorption of DX-9065a, a New Synthetic Anticoagulant
- 1 January 2007
- journal article
- Published by Japanese Society for the Study of Xenobiotics in Drug Metabolism and Pharmacokinetics
- Vol. 22 (1), 26-32
- https://doi.org/10.2133/dmpk.22.26
Abstract
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.Keywords
This publication has 14 references indexed in Scilit:
- ArgatrobanJournal of Thrombosis and Thrombolysis, 2002
- Intestinal Absorption of Azetirelin, a New Thyrotropin-Releasing Hormone (TRH) Analogue. I. Possible Factors for the Low Oral Bioavailability in Rats.Biological & Pharmaceutical Bulletin, 1994
- Effect of pH, Dietary Proteins and Trypsin Inhibitors on the Hydrolytic Rate of Human Granulocyte Colony-Stimulating Factor (G-CSF) by Rat Digestive Enzymes.Journal of Pharmacobio-Dynamics, 1991
- Investigations on plasma activity of low molecular weight heparin after intravenous and oral administrations.British Journal of Clinical Pharmacology, 1989
- Membrane permeability parameters for some amino acids and β-lactam antibiotics: Application of the boundary layer approachJournal of Theoretical Biology, 1988
- Determination of intrinsic membrane transport parameters from perfused intestine experiments: A boundary layer approach to estimating the aqueous and unbiased membrane permeabilitiesJournal of Theoretical Biology, 1988
- Estimating Human Oral Fraction Dose Absorbed: A Correlation Using Rat Intestinal Membrane Permeability for Passive and Carrier-Mediated CompoundsPharmaceutical Research, 1988
- Binding of antibiotics to rat intestinal mucinInternational Journal of Pharmaceutics, 1986
- Absorption Potential: Estimating the Fraction Absorbed for Orally Administered CompoundsJournal of Pharmaceutical Sciences, 1985
- Intestinal absorption mechanism of amino-.BETA.-lactam antibiotics. III. Kinetics of carrier-mediated transport across the rat small intestine in situ.Journal of Pharmacobio-Dynamics, 1984