Effects of pretreatment with the retinoid N-(4-hydroxyphenyl)-all-trans-retinamide and phenobarbital on the disposition and metabolism of N-(4-hydroxyphenyl)-all-trans-retinamide in mice.

The effects of pretreatment with N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR) and phenobarbital (PB) on the distribution and metabolism of 4-HPR, and on the levels of hepatic cytochromes, were investigated in female BDF mice. Pretreatment of mice for 3 days with 10 mg/kg 4-HPR had no effect on the disposition of 4-HPR in the serum, liver, mammary gland, or urinary bladder. 4-HPR pretreatment also had no effect on the pharmacokinetics of any of its metabolites in the liver, or on the levels of hepatic cytochromes P450 or b5. By contrast, pretreatment of mice for 3 days with 80 mg/kg PB had a significant effect on the disposition of 4-HPR in all the tissues examined; the areas under the concentration-time curves for PB-pretreated mice were half those for vehicle-pretreated mice. PB pretreatment also significantly reduced the levels of four metabolites of 4-HPR in the liver and increased the levels of hepatic cytochromes P450 and b5. These data suggest that prior or concomitant administration of drugs that induce the mixed function oxidase system could result in changes in retinoid disposition and metabolism; such changes may alter retinoid chemopreventive activity.