Distribution and metabolism of the retinoid, N-(4-methoxyphenyl)-all-trans-retinamide, the major metabolite of N-(4-hydroxyphenyl)-all-trans-retinamide, in female mice

Abstract

The metabolism and disposition of N-(4-methoxyphenyl)-all-trans-retinamide (MPR), the major metabolite of N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), were investigated in female B6D2F1 (BDF) mice. Following a single oral dose of 10 mg/kg, MPR distributed to the serum, liver, mammary gland, urinary bladder, and skin. The highest levels of MPR were detected in the liver and mammary gland, and the largest values for AUC were in the mammary gland followed by the skin and liver. The t1/2 for MPR was 5.1 hr in liver, 5.6 hr in serum, 18.7 hr in urinary bladder, 23.1 hr in skin, and 26.6 hr in mammary gland. MPR and five metabolites were detected; levels varied between tissues. One metabolite was 4-HPR; the other four, which eluted at 7, 12, 13, and 18 min, remain unidentified. The major metabolite of MPR was the 18-min metabolite and comprised 17% of total retinoid in skin and 14% in mammary gland. 4-HPR was only a minor metabolite of MPR; 4-HPR was not detectable in serum or urinary bladder and accounted for less than 4% of total retinoid in the other tissues. In mice dosed with 10 mg/kg 4-HPR, the parent compound, MPR, a putative 4-HPR ester, and three of the MPR metabolites (7, 13, and 18 min) were found. These data suggest that the interconversion of 4-HPR and MPR greatly favors formation of MPR.(ABSTRACT TRUNCATED AT 250 WORDS)