Gender Specific Drug Metabolism of PF-02341066 in Rats — Role of Sulfoconjugation

Abstract

PF-02341066 is a selective c-Met/Alk tyrosine kinase inhibitor currently in clinical development as an anticancer agent. Non-clinical toxicokinetic evaluation in rats revealed gender-related differences in pharmacokinetics with at least 2-fold higher PF-02341066 plasma concentrations in males than females when administered the same dose. In general, lower systemic exposure of drugs that undergoes oxidative metabolism in male than female rats has been well known to be attributed to gender-specific expression of CYP genes in rats. It is of interest to understand why the gender-related pharmacokinetics in rats for PF-02341066 was opposite to the general observations and if the gender-related pharmacokinetics would be seen in humans that may impact the drug efficacy and toxicity profiles. The potential gender-related differences in PF-02341066 metabolism were investigated both in vitro and in vivo using [(3)H]PF-02341066. Oxidation was found to be the major metabolic pathway in male rat liver S9 incubations whereas sulfoconjugation was the predominant metabolic pathway in females. There was no qualitative difference in metabolite profiles of PF-02341066 between man and woman liver S9 incubations. Following a single oral administration of [(3)H]PF-02341066 to rats at 150 mg/kg, the primary route of excretion of the radioactivity was via feces, in which, the most abundant radio-component in male rat was the parent drug (29% of dose) and in female rat was the parent sulfate (44% of dose). The more extensive formation of the parent sulfoconjugate in female rats most likely explains why the female rat had lower drug exposure compared to male rat, as gender-related changes of sulfotransferase expression were widely reported in rats. The human liver S9 study suggests that gender-related pharmacokinetics of PF-02341066 are unlikely to occur in humans.

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

“…However, a few studies revealed that female rats had higher clearance than male rats, which was due to the higher expression and activity of sulfotransferase in females, such as anticancer agent PF-02341066 (76). The pharmacokinetic evaluation of PF-02341066 in rats revealed the existence of gender-dependent differences with at least 2-fold higher plasma concentrations of PF-02341066 in male rats than that in female rats when the identical dose was administered, and the more extensive formation of the sulfoconjugated metabolite, mediated by the femalepredominant sulfotransferase, was assumed to be the major reason for the lower drug exposure of PF-02341066 in females (76). In addition, the gender-dependent pharmacokinetics in rats mediated by CYP2D has also been reported.…”

Liquid chromatography–tandem mass spectrometric assay for the ALK inhibitor crizotinib in mouse plasma

“…In rats and dogs, other oxidative metabolites like crizotinib-N-oxide (Supplemental Fig. 1) and hydroxy-crizotinib can additionally be observed [5,7]. In female rats, however, sulfated crizotinib is the main metabolite [7].…”

“…1) and hydroxy-crizotinib can additionally be observed [5,7]. In female rats, however, sulfated crizotinib is the main metabolite [7]. Pharmacokinetic data of this drug have been reported both in humans, the registered 250 mg twice daily oral administration of crizotinib resulted in average trough plasma levels of ca.…”

Excretion of [3H]triptolide and its metabolites in rats after oral administration

“…However, our results suggested that sulfation played a more important role in the metabolism of triptolide in female rats than that in male rats. This gender difference in triptolide metabolism was likely caused by the gender-specific expression of sulfotransferases in the rat [16][17][18] . In male rats, the triptolide GSH conjugate was detected as a major metabolite in bile.…”