title: Metabolic difference of CZ48 in human and mouse liver microsomes.
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.
authors: CHRISTUS Stehlin Foundation for Cancer Research, 10301 Stella Link, Houston, TX 77025, USA.
authors: Xing
authors: X
authors: Liu
authors: CHRISTUS Stehlin Foundation for Cancer Research, 10301 Stella Link, Houston, TX 77025, USA.
authors: Albert
authors: A
authors: DeJesus
authors: CHRISTUS Stehlin Foundation for Cancer Research, 10301 Stella Link, Houston, TX 77025, USA.
authors: Zhisong
authors: Z
authors: Cao
authors: CHRISTUS Stehlin Foundation for Cancer Research, 10301 Stella Link, Houston, TX 77025, USA.
authors: Dana
authors: D
authors: Vardeman
authors: CHRISTUS Stehlin Foundation for Cancer Research, 10301 Stella Link, Houston, TX 77025, USA.
authors: Beppino
authors: B
authors: Giovanella
mesh_terms: D000818:Animals; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D013045:Species Specificity
chemical_list: C532663:camptothecin, C20-propionate ester; D002166:Camptothecin