CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems.

Article Details

Citation

Wu Z, Lee D, Joo J, Shin JH, Kang W, Oh S, Lee do Y, Lee SJ, Yea SS, Lee HS, Lee T, Liu KH

CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems.

Antimicrob Agents Chemother. 2013 Nov;57(11):5448-56. doi: 10.1128/AAC.00843-13. Epub 2013 Aug 19.

PubMed ID
23959307 [ View in PubMed
]
Abstract

Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 mul/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 mul/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo.

DrugBank Data that Cites this Article

Drugs
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
AlbendazoleCytochrome P450 2C19ProteinHumans
No
Substrate
Details
ApixabanCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Details
ThioridazineCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Details
Drug Interactions
DrugsInteraction
Albendazole
Phenytoin
The serum concentration of the active metabolites of Albendazole can be reduced when Albendazole is used in combination with Phenytoin resulting in a loss in efficacy.
Albendazole
Fosphenytoin
The serum concentration of the active metabolites of Albendazole can be reduced when Albendazole is used in combination with Fosphenytoin resulting in a loss in efficacy.