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. 2012;13(5):5498-5505.
doi: 10.3390/ijms13055498. Epub 2012 May 8.

Metabolic difference of CZ48 in human and mouse liver microsomes

Xing Liu  1 , Albert DeJesus  1 , Zhisong Cao  1 , Dana Vardeman  1 , Beppino Giovanella  1
Affiliations

Metabolic difference of CZ48 in human and mouse liver microsomes

Xing Liu et al. Int J Mol Sci. 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 K(m)s of 1.9 and 0.5 nM and V(max)s 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.

Keywords: CZ48; UDP-glucuronosyltransferases; biotransformation; camptothecin; cytochromeP450; metabolism; microsomes.

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Figures

Figure 1
Figure 1
(a) Camptothecin (CPT) formation rate in human and mouse liver microsomes; (b) Accumulated formation of CPT in human and mouse liver microsomes. (a) (b)
Figure 2
Figure 2
(a) CPT formation rate in human and mouse liver microsomes in the presence of NADPH; (b) The kinetics of the CPT formation in human and mouse liver microsomes. (a) (b)
Figure 3
Figure 3
(a) Depletion rate of crystalline camptothecin-20-propionate (CZ48) in human and mouse liver microsomes in the presence of UDPGA. (b) CPT formation rate in human and mouse liver microsomes in the presence of UDPGA. (a) (b)
Figure 4
Figure 4
CYP-mediated metabolism of CZ48 to CPT.
See this image and copyright information in PMC

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