Pharmacokinetics of BAY 59-7939--an oral, direct Factor Xa inhibitor--in rats and dogs.
The pharmacokinetics of BAY 59-7939 - a novel, oral, direct Factor Xa inhibitor - were investigated in rats and dogs in support of preclinical safety studies and clinical development. BAY 59-7939 was rapidly absorbed after oral dosing, with an absolute bioavailability of 57-66% in rats, and 60-86% in dogs. Plasma pharmacokinetics of BAY 59-7939 were linear across the investigated dose range (1-10 mg kg(-1) in rats, 0.3-3 mg kg(-1) in dogs). Plasma clearance was low: 0.4 l kg(-1) h(-1) in rats and 0.3 l kg(-1) h(-1) in dogs; volume of distribution (V(ss)) was moderate: 0.3 l kg(-1) in rats, and 0.4 l kg(-1) in dogs. The elimination half-life after oral administration was short in both species (0.9-2.3 h). Whole-body autoradiography showed moderate tissue affinity. No retention or small volume enrichments of BAY 59-7939-related radioactivity were observed. The plasma-protein binding of BAY 59-7939 was high, species dependent and fully reversible. BAY 59-7939 was rapidly excreted in rats and dogs, and was not irreversibly retained. A dual mode of excretion (biliary/faecal and renal) was observed. In summary, BAY 59-7939 had a favourable, predictable pharmacokinetic profile, with high oral bioavailability and a dual route of excretion.
Weinz
C
C
Drug Metabolism and Isotope Chemistry, Bayer HealthCare AG, Wuppertal, Germany. corinna.weinz@bayerhealthcare.com
Buetehorn
U
U
Daehler
H-P
HP
Kohlsdorfer
C
C
Pleiss
U
U
Sandmann
S
S
Schlemmer
K-H
KH
Schwarz
T
T
Steinke
W
W
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065427:Factor Xa Inhibitors; D005260:Female; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000925:Anticoagulants; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban