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.
Highlights
Metabolism studies are essential in the drug discovery and development process and are important to safety studies for the clinical development of drug candidates
The conversion of CZ48 to CPT within 2 h in human versus mouse liver microsomes was investigated by incubating the agent in HLM and MLM, respectively, in the absence of NADPH
In the absence of NADPH, the depletion of CZ48 in mouse liver microsomes was faster than that in human liver microsomes. These results suggest that there is a remarkable species difference in CZ48 metabolism in liver microsomes between human and the mouse, and that the greater depletion rate of CZ48 in human liver microsomes is probably due to the involvement of human cytochrome P450s (CYPs); that is, the CZ48 metabolism in the human liver is probably a CYP-mediated process
Summary
Metabolism studies are essential in the drug discovery and development process and are important to safety studies for the clinical development of drug candidates. Hydrated crystalline camptothecin-20-propionate, CZ48, is under investigation for the treatment of cancer and is currently in phase 1 human clinical trials This agent has shown remarkable anticancer activity and a lack of toxicity in nude mice. We have pharmacokinetically analyzed the blood samples of 27 patients and observed that the concentration of CZ48 is 10 or more times lower in human blood than in the mouse, while the concentration of camptothecin (CPT) is multiple folds higher in human blood than in the mouse (our unpublished results) The cause for this is probably that CZ48 has been biotransformed differently in the human body compared to the mouse. A number of papers in literature report that human liver microsomes catalyze the metabolisms of different types of drugs. The information gained concerning the species differences from this study will be greatly helpful for extrapolating results from animals to humans
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