Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes
CZ48, chemically camptothecin-20-<em>O</em>-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 examine...
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doaj-7cfb8cc7819047cdba4b7f90b65230a82020-11-25T00:26:18ZengMDPI AGInternational Journal of Molecular Sciences1422-00672012-05-011355498550510.3390/ijms13055498Metabolic Difference of CZ48 in Human and Mouse Liver MicrosomesBeppino GiovanellaDana VardemanZhisong CaoAlbert DeJesusXing LiuCZ48, chemically camptothecin-20-<em>O</em>-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 <em>K</em><sub>m</sub>s of 1.9 and 0.5 nM and <em>V</em><sub>max</sub>s of 9.3 and 2.2 pmol/min/mg, respectively. However, the apparent intrinsic clearance (<em>V</em><sub>max</sub>/<em>K</em><sub>m</sub>) ratios for camptothecin in human and mouse liver microsomes were not significantly different from each other (4.9 <em>versus</em> 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.http://www.mdpi.com/1422-0067/13/5/5498metabolismbiotransformationcytochromeP450UDP-glucuronosyltransferasesmicrosomesCZ48camptothecin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Beppino Giovanella Dana Vardeman Zhisong Cao Albert DeJesus Xing Liu |
spellingShingle |
Beppino Giovanella Dana Vardeman Zhisong Cao Albert DeJesus Xing Liu Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes International Journal of Molecular Sciences metabolism biotransformation cytochromeP450 UDP-glucuronosyltransferases microsomes CZ48 camptothecin |
author_facet |
Beppino Giovanella Dana Vardeman Zhisong Cao Albert DeJesus Xing Liu |
author_sort |
Beppino Giovanella |
title |
Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes |
title_short |
Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes |
title_full |
Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes |
title_fullStr |
Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes |
title_full_unstemmed |
Metabolic Difference of CZ48 in Human and Mouse Liver Microsomes |
title_sort |
metabolic difference of cz48 in human and mouse liver microsomes |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2012-05-01 |
description |
CZ48, chemically camptothecin-20-<em>O</em>-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 <em>K</em><sub>m</sub>s of 1.9 and 0.5 nM and <em>V</em><sub>max</sub>s of 9.3 and 2.2 pmol/min/mg, respectively. However, the apparent intrinsic clearance (<em>V</em><sub>max</sub>/<em>K</em><sub>m</sub>) ratios for camptothecin in human and mouse liver microsomes were not significantly different from each other (4.9 <em>versus</em> 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. |
topic |
metabolism biotransformation cytochromeP450 UDP-glucuronosyltransferases microsomes CZ48 camptothecin |
url |
http://www.mdpi.com/1422-0067/13/5/5498 |
work_keys_str_mv |
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1725344888228151296 |