Studies on the metabolism and disposition of the new retinoid 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid. 3rd communication: placental transfer and excretion into milk in rats.
4-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid (CAS 94497-51-5, Am-80) is a new synthetic retinoid which has been shown to have a potent topical antipsoriatic activity. Placental transfer and excretion into milk after administration of 14C-Am-80 to pregnant or nursing rats were investigated in view of reproductive and developmental toxicity studies. When 14C-Am-80 was administered topically at a dose of 10 mg/kg to normal-skin pregnant rats on the 12th day of pregnancy, plasma 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, radioactivity 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 maternal plasma level of radioactivity and the concentration of radioactivity in the fetus up to 24 h after dosing rose about 10-fold in proportion to the increased dose. At both doses, the radioactivity level in the fetus at the peak corresponded to approximately one-third of the maternal plasma level. When 14C-Am-80 was administered subcutaneously at a dose of 1 mg/kg to pregnant rats on the 12th day of pregnancy, radioactivity in the fetus peaked at 4 h after dosing, being about one-fourth of the maternal plasma level at the same time point. Radioactivity in the fetus after subcutaneous administration of 14C-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-half the maternal plasma level at the same time point, and then decreased gradually. Among the fetal tissues, relatively high radioactivity was found in the liver. Whole-body autoradiography showed that in most tissues in the dam, the distribution pattern of radioactivity was similar to that in the non-pregnant rat. The concentration of radioactivity in the milk after subcutaneous administration of 14C-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. Unchanged Am-80 in the milk was largely recovered after hydrolysis of hexane extracts of the intact milk with lipase, suggesting extensive incorporation of Am-80 into the triglyceride in the milk because of its benzoic acid structure and high lipophilicity. As for radioactive metabolites which have hitherto been identified in rats, only M-6 (taurine conjugate of Am-80) and tetrahydro-tetra-methyl-naphthylamine (TTNA) were detectable in small amounts in the milk.
Mizojiri
K
K
New Drug Research Laboratories, Shionogi & Co., Ltd., Ibaraki, Japan.
Okabe
H
H
Sugeno
K
K
Esumi
Y
Y
Takaichi
M
M
Harada
T
T
Seki
H
H
Inaba
A
A
D000287:Administration, Topical; D000818:Animals; D001345:Autoradiography; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005333:Fetus / Q000378:metabolism; D007279:Injections, Subcutaneous; D007774:Lactation / Q000502:physiology; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D008892:Milk / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D001565:Benzoates; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C061133:tamibarotene