Interspecies differences in metabolism of deoxypodophyllotoxin in hepatic microsomes from human, monkey, rat, mouse and dog

Deoxypodophyllotoxin (DPT) is a natural lignan product which has drawn much attention due to its pharmacological properties including antitumor effect. The purpose of this study was to investigate interspecies differences in metabolism of DPT in hepatic microsomes from human (HLM), cynomolgus monkey...

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Published in:Drug metabolism and pharmacokinetics 2016-08, Vol.31 (4), p.314-322
Main Authors: Xie, Qiushi, Chen, Yang, Liu, Fei, Zhong, Zeyu, Zhao, Kaijing, Ling, Zhaoli, Wang, Fan, Tang, Xiange, Wang, Zhongjian, Liu, Li, Liu, Xiaodong
Format: Article
Language:English
Subjects:
Animals
Cytochrome P-450 Enzyme System - metabolism
Cytochrome P450s
Deoxypodophyllotoxin
Dogs
Hepatic microsomes
Humans
Interspecies differences
Isoenzymes - metabolism
Kinetics
Macaca fascicularis
Male
Metabolism
Mice
Microsomes, Liver - metabolism
Podophyllotoxin - analogs & derivatives
Podophyllotoxin - chemistry
Podophyllotoxin - metabolism
Rats
Rats, Sprague-Dawley
Species Specificity
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Summary:Deoxypodophyllotoxin (DPT) is a natural lignan product which has drawn much attention due to its pharmacological properties including antitumor effect. The purpose of this study was to investigate interspecies differences in metabolism of DPT in hepatic microsomes from human (HLM), cynomolgus monkey (CyLM), rat (RLM), mouse (MLM) and dog (DLM). Incubation of DPT with hepatic microsomes from five species in the presence of NADPH resulted in formation of seven metabolites, five of which were compared with the synthetic standards. M2 was the most abundant metabolite in microsomes from all species. Rank order of intrinsic clearance for M2 formation was RLM > CyLM > MLM > HLM > DLM. In HLM, sulfaphenazole showed the strongest inhibition effect on M2 formation, but neither ticlopidine nor ketoconazole inhibited M2 formation in HLM. Results from cDNA-expressed human CYP450s experiments showed that clearance of M2 formation was much higher in CYP2C9 and CYP2C19 than that in CYP3A4. Contributions of the three CYP450 isoforms to M2 formation in HLM were estimated using relative activity factor (RAF) method or correction by amount of CYP450 isoforms in HLM. M2 formation in HLM was mainly attributed to CYP2C9, followed by CYP2C19. Involvement of CYP3A4 was minor. [Display omitted]
ISSN:1347-4367
1880-0920
DOI:10.1016/j.dmpk.2016.05.002