Bexarotene metabolism in rat, dog, and human, synthesis of oxidative metabolites, and in vitro activity at retinoid receptors.

The metabolism of bexarotene, a rexinoid recently approved in the United States for treatment of cutaneous T-cell lymphoma, was studied using liver slices from untreated rats and dogs, liver microsomes from untreated and pretreated rats, and pooled human liver microsomes. Metabolite profiles were examined in bile and plasma from rats and dogs, and plasma from humans treated with bexarotene. Four metabolites, racemic 6-hydroxy-bexarotene, racemic 7-hydroxy-bexarotene, 6-oxo-bexarotene, and 7-oxo-bexarotene, were synthesized and their binding to, and transactivation of retinoid receptors were examined. Qualitatively similar metabolite profiles were observed in the microsomal and liver slice extracts; the predominant metabolites were 6-hydroxy-bexarotene and glucuronides of parent or hydroxylated metabolites. Pretreatment of rats with bexarotene induced hepatic microsomal bexarotene metabolism. The hydroxy and oxo metabolites were observed in plasma of rats, dogs, and humans treated with bexarotene and 6-hydroxy-bexarotene was a major circulating metabolite. The oxidative metabolites were more abundant relative to parent in plasma from humans than from rat or dog. The predominant biliary metabolites in rat and dog were bexarotene acyl glucuronide and a glucuronide of oxidized bexarotene, respectively. Since bexarotene elimination is primarily biliary in these species, these metabolites represent the main bexarotene metabolites in rats and dogs. The binding of synthetic metabolites to retinoid receptors was much reduced relative to parent compound. The metabolites exhibited minimal activity in transactivating retinoic acid receptors and had reduced activity at retinoid X receptors relative to bexarotene. Thus, while there is substantial systemic exposure to the oxidative metabolites of bexarotene, they are unlikely to elicit significant retinoid receptor activation following bexarotene administration.