Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes

International Journal of Molecular Sciences

Xing Liu²  Albert DeJesus²  Zhisong Cao¹  Dana Vardeman² 

[1] CHRISTUS Stehlin Foundation for Cancer Research, 10301 Stella Link, Houston, TX 77025, USA;

关键词: metabolism;    biotransformation;    cytochromeP450;    UDP-glucuronosyltransferases;    microsomes;    CZ48;    camptothecin;   

DOI  :  10.3390/ijms13055498

来源: mdpi

【 摘 要 】

CZ48, chemically camptothecin-20-O-propionate hydrate, is currently under clinical investigation. The kinetics of the metabolite camptothecin (CPT) formation and of CZ48 depletion in mouse and human liver microsomes in the presence or absence of NADPH was examined. The formation rate of camptothecin in human liver microsomes was significantly higher than that in mouse with mean K_ms of 1.9 and 0.5 nM and V_maxs of 9.3 and 2.2 pmol/min/mg, respectively. However, the apparent intrinsic clearance (V_max/K_m) ratios for camptothecin in human and mouse liver microsomes were not significantly different from each other (4.9 versus 4.4) in the presence of NADPH. The depletion of CZ48 in human microsomes was four times faster with 4.55% of CZ48 remaining intact while in mouse 19.11% of the drug remained unchanged after 60 min. These results suggest that there is a remarkable species difference of CZ48 biotransformation between human and mouse. The depletion rate of CZ48 in human liver microsomes is considerably higher than that in the mouse.

【 授权许可】

CC BY   
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.