STUDIES ON THE METABOLISM AND DISPOSITION OF THE NEW RETINOID TRAHYDRO-5,5,8,8-TETRAMETHYL-2-NAPHTHYL)CARBAMOYL] BENZOIC-ACID - 3RD COMMUNICATION - PLACENTAL-TRANSFER AND EXCRETION INTO MILK IN RATS

o-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid (GAS 94497-51- 5, Am-80) is a new synthetic retinoid which has been shown to have a p otent topical antipsoriatic activity. Placental transfer and excretion into milk after administration of C-14-Am-80 to pregnant or nursing r ats were investigated in view of reproductive and developmental toxici ty studies. When C-14-Am-80 was administered topically at a dose of 10 mg/kg to normal-skin pregnant rats on the 12th day of pregnancy, plas ma radioactivity in the dam and fetus was detected only at low levels. However, at a dose of 1 mg/kg to the stripped-skin pregnant rats, rad ioactivity levels peaked at 6 h in the maternal plasma (188.7 ng eq./g ) and fetus (64.6 ng eq./g) and at a dose of 10 mg/kg, the peak matern al plasma level of radioactivity and the concentration of radioactivit y in the fetus up to 24 h after dosing rose about 10-fold in proportio n to the increased dose. At both doses, the radioactivity level in the fetus at the peak corresponded to approximately one-third of the mate rnal plasma level. When C-14-Am-80 was administered subcutaneously at a dose of 1 mg/kg to pregnant rats on the 12th day of pregnancy, radio activity in the fetus peaked at 4 h after dosing, being about one-four th of the maternal plasma level at the same time point. Radioactivity in the fetus after subcutaneous administration of C-14-Am-80 at a dose of 1 mg/kg to pregnant rats on the 19th day of pregnancy peaked (156. 4 ng eq./g) at 4 h after dosing, corresponding to approximately one-ha lf the maternal plasma level at the same time point, and then decrease d gradually. Among the fetal tissues, relatively high radioactivity wa s found in the liver. Whole-body autoradiography showed that in most t issues in the dam, the distribution pattern of radioactivity was simil ar to that in the non-pregnant rat. The concentration of radioactivity in the milk after subcutaneous administration of C-14-Am-80 at a dose of 1 mg/kg to lactating rats on the 9th day after delivery peaked at 8 h after dosing, being 94 times greater than that in the plasma. Unch anged Am-80 in the milk was largely recovered after hydrolysis of hexa ne extracts of the intact milk with lipase, suggesting extensive incor poration of Am-80 into the triglyceride in the milk because of its ben zoic acid structure and high lipophilicity. As for radioactive metabol ites which have hitherto been identified in rats, only M-6 (taurine co njugate of Am-80) and tetrahydro-tetramethyl-naphthylamine (TTNA) were detectable in small amounts in the milk.