Pharmacokinetics and metabolism of the new thromboxane A2 receptor antagonist ramatroban in animals. 2nd communication: distribution to organs and tissues in male, female and pregnant rats, and characteristics of protein binding in plasma.
The distribution to organs and tissues, placental transfer and mammary excretion of ramatroban ((+)- (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid, CAS 116649-85-5, BAY u 3405) have been investigated in rats. Furthermore, the characteristics of protein binding in plasma of various species including man are described. After single oral administration of [14C]ramatroban to male rats, the radioactivity was preferentially localized in liver and kidneys, the tissue-to-plasma concentration ratios at tmax were 20 for liver and 6.3 for kidneys, respectively. For all other organs/tissues, a low to moderate affinity was detected. [14C]Ramatroban and its labeled metabolites did hardly penetrate the blood-brain barrier, and the brain-to-plasma concentration ratio was 0.03 at tmax. After repeated oral administration to male rats for 21 days, once daily, the radioactivity concentrations in organs and tissues showed only a slight tendency to accumulate. The AUC ratios in the dosing interval exhibited little or no increase, the highest accumulation factor was approximately 2. The steady-state of the trough levels in plasma was reached rapidly, with the third administration. The autoradiographic distribution pattern was not changed due to repeated administration. After receiving single oral doses of [14C]ramatroban, female rats showed almost identical autoradiographic distribution patterns of radioactivity compared with males. Although being similarly distributed, in most organs and tissues of pregnant rats (19th day of gestation) distinctly higher radioactivity concentrations were observed than in males. Maximal fetal concentrations occurred at 7 h after dosing. The distribution in fetuses was similar to that in maternal body, revealing relatively high concentrations in liver, kidneys, and gastrointestinal contents. The fetal AUC reached 68% of the AUC in maternal plasma. [14C]Ramatroban was excreted with the milk of lactating rats. The total amount within 24 h was estimated to be 1.7% of the maternal dose. [14C]Ramatroban is highly bound to plasma proteins in all species tested: rabbit (unbound fraction: 1.7-1.9%), rat (2.1-2.4%), man (2.0-2.7%), dog (2.4-2.8%), mouse (3.7-4.1%), guinea-pig (4.3-4.7%).
Steinke
W
W
Bayer AG, Pharma Product Development and Research, Wuppertal, Germany.
Ahr
H J
HJ
Hirayama
M
M
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001345:Autoradiography; D001798:Blood Proteins / Q000378:metabolism; D002227:Carbazoles / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008892:Milk / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D013928:Thromboxane A2 / Q000378:metabolism*; D014018:Tissue Distribution
D001798:Blood Proteins; D002227:Carbazoles; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013928:Thromboxane A2; C063119:ramatroban