Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid
Abstract
OBJECTIVE: The effects of various polymorphisms in cytochrome P450 (CYP) enzyme and transporter genes on the pharmacokinetics (PK) of simvastatin were evaluated in healthy Korean men. METHODS: Plasma concentration data for simvastatin and simvastatin acid were pooled from four phase I studies comprising 133 participants. The polymorphisms CYP2D6*4, CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, CYP2C19*2, CYP2C19*3, CYP2A6*7, and CYP2A6*9; SLCO1B1 rs4149056, rs2306283, and rs4149015; ABCB1 rs1128503, rs2032582, and rs1045642; and ABCG2 rs2231142 were evaluated in each participant. Noncompartmental PK results were compared by genotype. RESULTS: CYP2D6*5 and CYP2D6*14 were found to be associated with a higher area under the curve (AUC) for simvastatin, whereas the AUC of simvastatin acid was significantly increased in patients with the SLCO1B1 rs4149056, ABCG2 rs2231142, and CYP2D6*41 allele variants. Patients with the CYP2D6*41 variant showed a higher peak serum concentration (Cmax) of both simvastatin and simvastatin acid. The SLCO1B1 rs4149056 and rs4149015 polymorphisms were associated with an increased AUC ratio (i.e. ratio of simvastatin acid to simvastatin), whereas the SLCO1B1 rs4149056 and CYP2D6*5 variants were related to a higher Cmax ratio. CONCLUSION: The CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, SLCO1B1 rs4149056 and rs4149015, and ABCG2 rs2231142 genetic polymorphisms are associated with the PK of both simvastatin and simvastatin acid. This could potentially be used as a basis for individualized simvastatin therapy by predicting the clinical outcomes of this treatment.
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Several DGI studies describe an association between SVL disposition and BCRP transporter polymorphisms, but findings are inconsistent and the clinical importance is still highly debatable.
“Although several DGI studies describe an association between SVL disposition and BCRP transporter polymorphisms, 29 , 30 , 34 , 36 findings are inconsistent and the clinical importance is still highly debatable.”
From Does the choice of applied physiologically‐based pharmacokinetics platform matter? A case study on simvastatin disposition and drug–drug interaction (2022) · cites this paper as [30]
There are DDI and DGI studies demonstrating SVA influx to hepatocytes via the membrane transporter OATP1B1.
“Additionally, there are DDI and drug–gene interaction (DGI) studies demonstrating SVA influx to hepatocytes via the membrane transporter OATP1B1. 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35”
From Does the choice of applied physiologically‐based pharmacokinetics platform matter? A case study on simvastatin disposition and drug–drug interaction (2022) · cites this paper as [30]
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Prieto Garcia, L., Lundahl, A., Ahlström, C., Vildhede, A., Lennernäs, H., & Sjögren, E. (2022) · CPT: Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.12837 · Cited by 21 · see citing works
- Authors
- Choi, H. Y., Bae, K.-S., Cho, S.-H., Ghim, J.-L., Choe, S., Jung, J. A., Jin, S.-J., Kim, H.-S., & Lim, H.-S.
- Affiliations
- Inha University (KR)
- Asan Medical Center (KR)
- Inje University Busan Paik Hospital (KR)
- Pusan National University (KR)
- Daewoong Pharmaceutical (South Korea) (KR)
- Corresponding author
- Lim, Hyeong-Seok
- ORCID
- Venue
- Pharmacogenetics and Genomics
- Published
- 2015-12
- Volume
- 25
- Issue
- 12
- Pages
- 595-608
- ISSN
- 1744-6872 (ISSN-L)
- OpenAlex
- W2402156517
- Cited by
- 49
- References
- 5
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 13 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 6 · 2018: 6 · 2017: 3 · 2016: 2
- FWCI
- 4.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacogenetics and Genomics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- simvastatin, simvastatin acid, pharmacokinetics, genetic polymorphism, CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, P-glycoprotein, ABCG2, drug metabolism, statins
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Adult, Dose-Response Relationship, Drug, Humans, Male, Neoplasm Proteins, ATP Binding Cassette Transporter, Subfamily B, ATP-Binding Cassette Transporters, Cytochrome P-450 CYP2D6, Simvastatin, Polymorphism, Single Nucleotide, Organic Anion Transporters, Liver-Specific Organic Anion Transporter 1, Cytochrome P-450 CYP3A, Young Adult, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2C19
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