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. 1st communication: absorption, distribution, metabolism and excretion after topical application and subcutaneous administration 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. The pharmacokinetic profiles of Am-80 were studied in rats after topical application and subcutaneous administration of 14C-labeled Am-80. After topical application at a dose of 1 g ointment (0.1%)/kg to normal skin rats by the occlusive dressing technique, radioactivity was scarcely detected in the blood or plasma. In the stripped skin rats, plasma radioactivity reached the peak at 2 h and decreased with a half-life of 5.5 h. The recovery of radioactivity in the excreta and carcass amounted to 54.7% of the dose, indicating about six times higher absorption than that in the normal skin rats. After subcutaneous administration at a dose of 1 mg/kg, the maximum concentration of blood radioactivity was attained at 1-2 h and declined with a half-life of 4-5 h until 24 h. Biliary excretion was about 80% of the dose, and enterohepatic circulation was estimated to be 36.5%. Radioactivity was distributed systemically, particularly in abundance in the liver followed by adrenal gland and kidney. Elimination of radioactivity in most tissues was extremely slow and the radioactivity was detected even at 240 h after dosing. There was no gender-related difference in the profile of distribution and elimination of 14C-Am-80 in the rats. Two major metabolic pathways in rats have been postulated for Am-80; one involves the 6- or 7-hydroxylation to yield related hydroxy-Am-80 that lead to the formation of oxo-Am-80, and another involves the hydrolysis of the carboxamide bond to yield tetrahydro-tetramethyl-naphthalenylamine and terephthalic acid. Furthermore, Am-80 itself an 6- or 7-hydroxy-Am-80 were susceptible to the formation of taurine conjugates. In the plasma, unchanged Am-80 was present in a high proportion to total radioactivity, while in the urine and bile the proportion of unchanged Am-80 was low.
Mizojiri
K
K
Process R&D Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Okabe
H
H
Sugeno
K
K
Esumi
Y
Y
Takaichi
M
M
Miyake
T
T
Seki
H
H
Inaba
A
A
D000287:Administration, Topical; D000818:Animals; D001345:Autoradiography; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004764:Enterohepatic Circulation / Q000502:physiology; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D007279:Injections, Subcutaneous; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D001565:Benzoates; D003879:Dermatologic Agents; D013764:Tetrahydronaphthalenes; C061133:tamibarotene