Metabolism of roquinimex in mouse and rat: an in vitro/in vivo comparison.

1.1. In vitro studies with roquinimex, an immune-modulator, in liver microsomes from mouse and rat were conducted to evaluate the primary metabolism and compare the metabolite pattern as well as the rate of metabolism with the in vivo pharmacokinetics of the compound in these two species. 2. In the presence of NADPH, roquinimex was metabolized to six primary metabolites (R1-6) by liver microsomes from mouse and rat. The formation of these metabolites was qualitatively similar in both species, and was greatly enhanced by pretreatment with PCN, an inducer of cytochrome P4503A. 3. The identification of the R1-6 demonstrated that roquinimex had been hydroxylated and demethylated. Hydroxylation at different sites of the quinoline moiety was the dominating reaction in both species. 4. Comparison of the resulting microsomal intrinsic clearance of 0.3 mu mol mg(-1) protein min(-1) in mouse liver microsomes, versus 0.03 mu mol mg(-1) protein min(-1) in rat liver microsomes demonstrated that the mouse possesses about a 10-fold greater metabolic capacity for roquinimex than the rat. 5. The Ga vivo pharmacokinetics of roquinimex demonstrated a 7-fold higher clearance in mouse than in the rat (82 ml h(-1) kg(-1) in mouse, 10.6 mi h(-1) kg(-1) in rat), which is in concordance with the in vitro findings.