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. 2nd communication: absorption, distribution and excretion after single and consecutive 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 antisporiatic activity. The accumulation characteristics of Am-80 were examined in rats after a single and consecutive subcutaneous administration of 14C-labeled Am-80 once a day for 24 days, at a daily dose of 0.2 mg/kg. As compared with the single administration, Tmax (1-2 h) and Cmax (about 50 ng eq./ml) of the blood radioactivity were not altered markedly after the consecutive administration. During the daily subcutaneous dosing, the blood level of radioactivity at 24 h after each dosing was also very low. These findings suggested that accumulation in the blood was low after long term consecutive administration of Am-80. The plasma levels of total radioactivity and the proportion of unchanged Am-80 to the total plasma radioactivity, being about 80% at 2 h after administration, and plasma elimination half-life of Am-80, being approximately 3 h, appeared to be hardly affected by the consecutive administration. The cumulative excretion of radioactivity at 168 h after the final dosing was 6.7% and 89.1% in the urine and feces, respectively. The radioactivity remaining in the carcass at this time was about 3% of the total dose. The excretion profile was not altered by the consecutive administration. In most tissues, the concentration of radioactivity at 24 h after each dose reached a steady-state within 24 doses. At 2 h after the consecutive administration for 24 days, the highest concentration of radioactivity was found in the liver followed by the adrenal gland. Accumulation and delayed elimination of radioactivity in most tissues, especially in the adrenal gland, fat, skin and epididymis, were evidently observed as predicted from the previous study where 14C-Am-80 was administered at a dose of 1 mg/kg. The profile of accumulation and retention of radioactivity after the consecutive administration may be considered as a common characteristic of retinoids, such as etretinate.
Mizojiri
K
K
New Drug Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Okabe
H
H
Sugeno
K
K
Esumi
Y
Y
Takaichi
M
M
Tsutsumi
S
S
Harada
T
T
Miyoshi
R
R
Inaba
A
A
D000818:Animals; D001345:Autoradiography; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D012869:Skin Absorption; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution
D001565:Benzoates; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C061133:tamibarotene