title: Characterization of in vitro biotransformation of the new oral anticoagulants, the factor VIIa inhibitors AS1927819-00 and AS1932804-00.
abstract: We recently developed a prodrug (AS1932804-00, CMP) of the novel FVIIa inhibitor AS1924269-00, which possesses a carbamate amidine backbone. In addition, we developed another type of prodrug (AS1927819-00, OXP) with an oxime amidine backbone. In this study, we investigated the efficiency of conversion of these novel FVIIa prodrugs to their active forms by evaluating the production of the active form in vitro by using microsomes, mitochondria, and cryopreserved hepatocytes, and compared it with the in vivo conversion mechanisms of the prodrugs (oxime amidine vs. carbamate amidine). We observed that OXP and CMP showed improved oral absorption, and the efficiency of conversion of CMP to the active form was higher than that of OXP. The in vivo rate of conversion of OXP to its active form was low in rats, and compared to liver microsomes and mitochondria, cryopreserved hepatocytes supplemented with serum and coenzymes were an appropriate metabolic test tool. On the other hand, the efficiency of conversion of CMP to its active from could be appropriately evaluated using small intestinal microsomes. The development of a prodrug can be optimized when information about the stability of carboxylic acid esters in the presence of serum esterases, membrane permeability of intermediate forms, and differential tissue specificity to metabolic activities for carbamate and oxime backbones of amidine can be obtained.
authors.affiliation: Pharmacokinetics Research Laboratories, Kissei Pharmaceutical Co., Ltd., 19-48 Yoshino, 399-8710 Matsumoto-City, Nagano-Pref, Japan. takeshi_nakabayashi@pharm.kissei.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Nakabayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Gotoh
authors.forename: N
authors.initials: N
authors.lastname: Kamada
authors.forename: M
authors.initials: M
authors.lastname: Fujioka
authors.forename: T
authors.initials: T
authors.lastname: Ishihara
authors.forename: A
authors.initials: A
authors.lastname: Hirabayashi
authors.forename: H
authors.initials: H
authors.lastname: Sato
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics*; D001384:Azetidines / Q000493:pharmacokinetics; D001596:Benzylamines / Q000493:pharmacokinetics; D001711:Biotransformation; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000378:metabolism; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010642:Phenoxyacetates / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000378:metabolism; D051381:Rats
chemical_list: C582794:AS1927819-00; C582793:AS1932804-00; D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D010642:Phenoxyacetates; D011355:Prodrugs; D009243:NAD; C426686:ximelagatran; D009249:NADP; D015942:Factor VIIa