Reference

Pharmacokinetics and metabolism of the new thromboxane A2 receptor antagonist ramatroban in animals

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. Steinke, Wolfram; Ahr, Hans Jurgen; Hirayama, Masashi (Bayer A.-G., Wuppertal, Germany). Arzneimittel-Forschung, 47(8), 939-948 (English) 1997 Cantor. CODEN: ARZNAD. ISSN: 0004-4172. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The distribution to organs and tissues, placental transfer and mammary excretion of ramatroban ((+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazole propanoic 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 concn. ratios at tmax were 20 for liver and 6.3 for kidneys, resp. 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 concn. ratio was 0.03 at tmax. After repeated oral administration to male rats for 21 days, once daily, the radioactivity concns. 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 approx. 2. The steady-state of the trough levels in plasma was reached rapidly, with the third administration. The autoradiog. distribution pattern was not changed due to repeated administration. After receiving single oral doses of [14C]ramatroban, female rats showed almost identical autoradiog. 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 concns. were obsd. than in males. Maximal fetal concns. occurred at 7 h after dosing. The distribution in fetuses was similar to that in maternal body, revealing relatively high concns. 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 amt. within 24 h was estd. 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%).

Pharmacokinetics and metabolism of the new thromboxane A2 receptor antagonist ramatroban in animals

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. Boberg, Michael; Ahr, Hans Jurgen; Beckermann, Bernhard; Buhner, Klaus; Siefert, Hans Martin; Steinke, Wolfram; Wunsche, Christian; Hirayama, Masashi (Bayer A.-G., Wuppertal, Germany). Arzneimittel-Forschung, 47(8), 928-938 (English) 1997 Cantor. CODEN: ARZNAD. ISSN: 0004-4172. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The absorption, concns. in plasma, metab. and excretion of ramatroban ((+)-(3R)-3-(4-fluoro-phenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazole propanoic acid, CAS 116649-85-5, BAY u 3405) have been studied following a single i.v., oral, or intraduodenal administration of 14C-labeled or non-labeled compd. 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 obsd. in rats. The elimination of the parent compd. 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 obsd. 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 compd., as well as 3-fold higher renal excretion of total radioactivity was obsd. A marked species difference exists in the metab. of ramatroban. In dogs the drug was almost exclusively metabolized via conjugation with glucuronic acid, whereas in rats oxidative phase I metab. 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).