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Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro: a different effect on asunaprevir versus daclatasvir and beclabuvir.
- Source :
-
Journal of human genetics [J Hum Genet] 2020 Jan; Vol. 65 (2), pp. 143-153. Date of Electronic Publication: 2019 Oct 23. - Publication Year :
- 2020
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Abstract
- Direct-acting antivirals, asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are known to be mainly metabolized by CYP3A enzymes; however, the differences in the detailed metabolic activities of CYP3A4 and CYP3A5 on these drugs are not well clarified. The aim of the present study was to elucidate the relative contributions of CYP3A4 and CYP3A5 to the metabolism of ASV, DCV, and BCV, as well as the effect of CYP3A5*3 genetic variant in vitro. The amount of each drug and their major metabolites were determined using LC-MS/MS. Recombinant CYP3As and CYP3A5*3-genotyped human liver microsomes (CYP3A5 expressers or non-expressers) were used for the determination of their metabolic activities. The contribution of CYP3A5 to ASV metabolism was considerable compared to that of CYP3A4. Consistently, ASV metabolic activity in CYP3A5 expressers was higher than those in CYP3A5 non-expresser. Moreover, CYP3A5 expression level was significantly correlated with ASV metabolism. In contrast, these observations were not found in DCV and BCV metabolism. To our knowledge, this is the first study to directly demonstrate the effect of CYP3A5*3 genetic variants on the metabolism of ASV. The findings of the present study may provide basic information on ASV, DCV, and BCV metabolisms.
- Subjects :
- Benzazepines chemistry
Carbamates
Chromatography, Liquid
Cytochrome P-450 CYP3A metabolism
Genetic Variation
Genotype
Humans
Imidazoles chemistry
Indoles chemistry
Isoquinolines chemistry
Liver metabolism
Microsomes, Liver
Pyrrolidines
Recombinant Proteins
Sulfonamides chemistry
Tandem Mass Spectrometry
Valine analogs & derivatives
Antiviral Agents metabolism
Benzazepines metabolism
Cytochrome P-450 CYP3A genetics
Imidazoles metabolism
Indoles metabolism
Isoquinolines metabolism
Sulfonamides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1435-232X
- Volume :
- 65
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 31645655
- Full Text :
- https://doi.org/10.1038/s10038-019-0685-2