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Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes
CHRISTUS Stehlin Foundation for Cancer Research, 10301 Stella Link, Houston, TX 77025, USA
* Author to whom correspondence should be addressed.
Received: 27 March 2012; in revised form: 27 April 2012 / Accepted: 28 April 2012 / Published: 8 May 2012
Abstract: 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 Kms of 1.9 and 0.5 nM and Vmaxs of 9.3 and 2.2 pmol/min/mg, respectively. However, the apparent intrinsic clearance (Vmax/Km) 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.
Keywords: metabolism; biotransformation; cytochromeP450; UDP-glucuronosyltransferases; microsomes; CZ48; camptothecin
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Liu, X.; DeJesus, A.; Cao, Z.; Vardeman, D.; Giovanella, B. Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes. Int. J. Mol. Sci. 2012, 13, 5498-5505.
Liu X, DeJesus A, Cao Z, Vardeman D, Giovanella B. Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes. International Journal of Molecular Sciences. 2012; 13(5):5498-5505.
Liu, Xing; DeJesus, Albert; Cao, Zhisong; Vardeman, Dana; Giovanella, Beppino. 2012. "Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes." Int. J. Mol. Sci. 13, no. 5: 5498-5505.