Induction of hepatic <scp>CYP3A4</scp> expression by cholesterol and cholic acid: Alterations of gene expression, microsomal activity, and pharmacokinetics

Minegishi, Genki; Kobayashi, Yuka; Fujikura, Mayu; Sano, Ayane; Kazuki, Yasuhiro; Kobayashi, Kaoru

doi:10.1002/prp2.1197

Cited by 2 publications

(1 citation statement)

References 56 publications

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“…The expression and activities of CYP‐enzymes are influenced by various factors, including genetics, diet, environment, and ethnicity. 9 , 26 It is valuable to explore data for Chinese outside of China. An analysis of gene polymorphisms among Chinese, Malays, and Indians in Singapore showed that pharmacogenetics of drug‐metabolizing enzymes in Asian populations differed significantly from Caucasian and African populations.…”

Section: Discussionmentioning

confidence: 99%

An open‐label study to explore the optimal design of CYP3A drug–drug interaction clinical trials in healthy Chinese people

Chen,

Li,

et al. 2024

Pharmacology Res & Perspec

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A drug–drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early‐phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three‐cycle, self‐controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1‐hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21‐fold based on maximum plasma concentration (Cmax), 8.37‐fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC0–t), and 11.22‐fold based on area under the curve from zero to infinity (AUC0–∞). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27‐fold based on Cmax, ~0.18‐fold based on AUC0–t, and ~0.18‐fold based on AUC0–∞. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near‐maximal CYP3A levels.

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Section: Discussionmentioning

confidence: 99%

An open‐label study to explore the optimal design of CYP3A drug–drug interaction clinical trials in healthy Chinese people

Chen,

Li,

et al. 2024

Pharmacology Res & Perspec

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Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron

Soria-Chacartegui,

Cendoya-Ramiro,

González-Iglesias

et al. 2024

Pharmaceutics

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Mirabegron is a drug used in overactive bladder (OAB) treatment. Genetic variation in pharmacogenes might alter its pharmacokinetics, affecting its efficacy and safety. This research aimed to analyze the impact of genetic variation on mirabegron pharmacokinetics and safety. Volunteers from three bioequivalence trials (n = 79), treated with a single or a multiple dose of mirabegron 50 mg under fed or fasting conditions, were genotyped for 115 variants in pharmacogenes and their phenotypes were inferred. A statistical analysis was performed, searching for associations between genetics, pharmacokinetics and safety. CYP2D6 intermediate metabolizers showed a higher elimination half-life (t1/2) (univariate p-value (puv) = 0.018) and incidence of adverse reactions (ADRs) (puv = 0.008, multivariate p (pmv) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t1/2 than the T/T genotype (puv = 0.002, pmv = 0.003). A lower dose/weight corrected area under the curve (AUC/DW) and higher clearance (CL/F) were observed in the SLC6A2 rs12708954 C/C genotype compared to the C/A genotype (puv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased (puv = 0.007, pmv = 0.010). The lower elimination and higher ADR incidence when CYP2D6 activity is reduced suggest it might be a useful biomarker in mirabegron treatment. UGT1A4, SLC6A2 and SLCO1B1 might also be involved in mirabegron pharmacokinetics.

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Induction of hepatic CYP3A4 expression by cholesterol and cholic acid: Alterations of gene expression, microsomal activity, and pharmacokinetics

Cited by 2 publications

References 56 publications

An open‐label study to explore the optimal design of CYP3A drug–drug interaction clinical trials in healthy Chinese people

An open‐label study to explore the optimal design of CYP3A drug–drug interaction clinical trials in healthy Chinese people

Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron

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