Gender specific drug metabolism of PF-02341066 in rats--role of sulfoconjugation.
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.
Zhong
Wei-Zhu
WZ
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, San Diego, CA 92121, USA. wei-zhu.zhong@pfizer.com
Zhan
Jenny
J
Kang
Ping
P
Yamazaki
Shinji
S
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D000077547:Crizotinib; D004285:Dogs; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010084:Oxidation-Reduction; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D011725:Pyridines / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013045:Species Specificity; D013431:Sulfates / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D013431:Sulfates; D000077547:Crizotinib; D015238:Sulfotransferases