TY - JOUR
T1 - Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro
T2 - a different effect on asunaprevir versus daclatasvir and beclabuvir
AU - Matsumoto, Jun
AU - San, Su Nwe
AU - Fujiyoshi, Masachika
AU - Kawauchi, Ayano
AU - Chiba, Natsumi
AU - Tagai, Ran
AU - Sanbe, Ryoko
AU - Yanaka, Shiho
AU - Sakaue, Hiroaki
AU - Kato, Yoshinori
AU - Nakamura, Hiroyoshi
AU - Yamada, Harumi
AU - Ariyoshi, Noritaka
N1 - Funding Information:
The authors would like to thank the financial support from the Ministry of Science and Technology of Taiwan (contract no. MOST 107‐2113‐M‐126‐004‐MY2 and MOST 107‐2221‐E‐009‐112‐MY3).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to The Japan Society of Human Genetics.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s10038-019-0685-2
DO - 10.1038/s10038-019-0685-2
M3 - Article
C2 - 31645655
AN - SCOPUS:85074212413
SN - 1434-5161
VL - 65
SP - 143
EP - 153
JO - Jinrui idengaku zasshi. The Japanese journal of human genetics
JF - Jinrui idengaku zasshi. The Japanese journal of human genetics
IS - 2
ER -