PHARMACOKINETICS AND METABOLISM OF THE NEW THROMBOXANE A(2) RECEPTOR ANTAGONIST RAMATROBAN IN ANIMALS - 2ND COMMUNICATION - DISTRIBUTION TOORGANS 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 lfonamido)-1,2,3,4-tetrahydro-9-carbazoleprop anoic acid, CAS 116649-85-5, BAY u 3405) have been investigated in rat s. Furthermore, the characteristics of protein binding in plasma of va rious species including man are described. After single oral administr ation of [C-14]ramatroban to male rats, the radioactivity was preferen tially localized in liver and kidneys, the tissue-to-plasma concentrat ion ratios at t(max) were 20 for liver and 6.3 for kidneys, respective ly For all other organs/tissues, a low to moderate affinity was detect ed. [C-14]Ramatroban and its labeled metabolites did hardly penetrate the blood-brain barrier, and the brain-to-plasma concentration ratio w as 0.03 at t(max). After repeated oral administration to male rats for 21 days, once daily, the radioactivity concentrations in organs and t issues showed only a slight tendency to accumulate. The AUC ratios in the dosing interval exhibited little or no increase, the highest accum ulation factor was approximately 2. The steady-state of the trough lev els 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 [C-14]ramatroban, female rats showed almost identical autoradiographic distribution pat terns of radioactivity compared with males. Although being similarly d istributed, in most organs and tissues of pregnant rats (19th day of g estation) distinctly higher radioactivity concentrations were observed than in males. Maximal fetal concentrations occurred at 7 h after dos ing. The distribution in Fetuses was similar to that in maternal body, revealing relatively high concentrations in liver, kidneys, and gastr ointestinal contents. The fetal AUC reached 68% of the AUC in maternal plasma. [C-14]Ramatroban was excreted with the milk of lactating rats . The total amount within 24 h was estimated to be 1.7% of the materna l dose. [C-14]Ramatroban is highly bound to plasma proteins in all spe cies 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%).