In vivo and in vitro evidence of the sex-dependent pharmacokinetics and disposition of G004, a potential hypoglycemic agent, in rats.
G004 is a novel sulfonylurea hypoglycemic drug which aimed at reducing macro- and micro-vascular complications as well as controlling glucose excursion in type 2 diabetes mellitus. The pharmacokinetics of G004 in rats was sex- and dose-dependent over the dose range of 1-10 mg kg(-1). The mean AUC values in the female rats were fivefold higher than those in males. Drug blood and tissue levels in female rats were higher than the most counterparts of males. Compared with male rats, G004 was eliminated slowly from female rats in the bile, urine and feces. Consistent with the in vivo observations, marked sex-related difference of the metabolizing activity between the male and female liver microsomes (RLM) was observed. The intrinsic clearance (V max/K m) of G004 was 3.1-fold larger in the RLM from male than female rats. Seventeen oxidative metabolites were identified in rat liver microsomes. The amount of three metabolites of G004 showed relatively sex-related difference in RLM incubations. CYP2C11 was demonstrated mainly contributing to the sex-related differences in the pharmacokinetics and disposition of G004 in rats.
Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
Linlin
L
Hu
Janvier Engelbert
JE
Agbokponto
Xiaobing
X
Li
Li
L
Ding
Bing
B
Liu
Shuisheng
S
Zhong
Xiaoyu
X
Zhang
Yiwei
Y
Du
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D005260:Female; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013453:Sulfonylurea Compounds / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D001798:Blood Proteins; C000600709:G004 compound; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D003577:Cytochrome P-450 Enzyme System