Pharmacokinetics and metabolism of the new thromboxane A2 receptor antagonist ramatroban in animals. 1st communication: absorption, concentrations in plasma, metabolism, and excretion after single administration to rats and dogs.
The absorption, concentrations in plasma, metabolism and excretion of ramatroban ((+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid, CAS 116649-85-5, BAY u 3405) have been studied following a single intravenous, oral, or intraduodenal administration of 14C-labeled or nonlabeled compound to rats and dogs (dose range: 1-10 mg.kg-1). After intraduodenal administration of [14C]ramatroban, enteral absorption of radioactivity was rapid and almost complete both in bile duct-cannulated male rats (83%) and female dogs (95%). The oral bioavailability of ramatroban was complete in the dog but amounted to about 50% in the rat due to presystemic elimination. A marked food effect on the rate but not on the extent of absorption was observed in rats. The elimination of the parent compound from plasma occurred rapidly with total clearance of 1.2 l.h-1.kg-1 in male rats and 0.7 l.h-1.kg-1 in dogs. After oral administration to male rats AUC increased dose-proportionally between 1 and 10 mg.kg-1, whereas in Cmax an over-proportional increase was observed. Excretion of total radioactivity was fast and occurred predominantly via the biliary/fecal route in both species. The residues were low, 144 h after dosing less than 0.2% of the radioactivity remained in the body of rats. A considerable sex difference was found in rats following oral administration of ramatroban. In females a 3-fold higher AUC and a 1.7-fold longer half-life of unchanged compound, as well as 3-fold higher renal excretion of total radioactivity was observed. A marked species difference exists in the metabolism of ramatroban. In dogs the drug was almost exclusively metabolized via conjugation with glucuronic acid, whereas in rats oxidative phase I metabolism and glucuronidation were equally important. As a consequence enterohepatic circulation was much more pronounced in dogs (77%) than in rats (17% of the initial dose).
Boberg
M
M
Bayer AG, Pharma Product Development and Research, Wuppertal, Germany.
Ahr
H J
HJ
Beckermann
B
B
Bühner
K
K
Siefert
H M
HM
Steinke
W
W
Wünsche
C
C
Hirayama
M
M
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D002227:Carbazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004764:Enterohepatic Circulation; D005260:Female; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008099:Liver / Q000166:cytology / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012727:Sex Characteristics; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013928:Thromboxane A2 / Q000378:metabolism*
D002227:Carbazoles; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013928:Thromboxane A2; C063119:ramatroban