Abstract

Abstract The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S- and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 ? 10-9 and P = 3.19 ? 10-12). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34% per variant allele copy; P = 8.15 ? 10-8). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single nucleotide variations (SNVs) may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity. This article is protected by copyright. All rights reserved.
Original languageEnglish
JournalClinical Pharmacology and Therapeutics
ISSN0009-9236
DOIs
Publication statusPublished - 16 Apr 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • fluvastatin
  • CYP2C9
  • SLCO1B1
  • pharmacokinetics
  • pharmacogenomics
  • genotype score
  • massive parallel sequencing
  • next generation sequencing
  • 317 Pharmacy

Cite this

@article{d450114724174dd1b4c612b22742b719,
title = "Enantiospecific pharmacogenomics of fluvastatin",
abstract = "Abstract The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S- and 3S,5R-fluvastatin (by 67{\%} and 94{\%} per variant allele copy, P = 3.77 ? 10-9 and P = 3.19 ? 10-12). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34{\%} per variant allele copy; P = 8.15 ? 10-8). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single nucleotide variations (SNVs) may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity. This article is protected by copyright. All rights reserved.",
keywords = "fluvastatin, CYP2C9, SLCO1B1, pharmacokinetics, pharmacogenomics, genotype score, massive parallel sequencing, next generation sequencing, 317 Pharmacy",
author = "P{\"a}ivi Hirvensalo and Aleksi Tornio and Mikko Neuvonen and Wilma Kiander and Heidi Kidron and Maria Paile-Hyv{\"a}rinen and Tuija Tapaninen and Backman, {Janne T.} and Mikko Niemi",
year = "2019",
month = "4",
day = "16",
doi = "10.1002/cpt.1463",
language = "English",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Wiley",

}

Enantiospecific pharmacogenomics of fluvastatin. / Hirvensalo, Päivi; Tornio, Aleksi; Neuvonen, Mikko; Kiander, Wilma; Kidron, Heidi; Paile-Hyvärinen, Maria; Tapaninen, Tuija; Backman, Janne T.; Niemi, Mikko.

In: Clinical Pharmacology and Therapeutics, 16.04.2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Enantiospecific pharmacogenomics of fluvastatin

AU - Hirvensalo, Päivi

AU - Tornio, Aleksi

AU - Neuvonen, Mikko

AU - Kiander, Wilma

AU - Kidron, Heidi

AU - Paile-Hyvärinen, Maria

AU - Tapaninen, Tuija

AU - Backman, Janne T.

AU - Niemi, Mikko

PY - 2019/4/16

Y1 - 2019/4/16

N2 - Abstract The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S- and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 ? 10-9 and P = 3.19 ? 10-12). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34% per variant allele copy; P = 8.15 ? 10-8). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single nucleotide variations (SNVs) may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity. This article is protected by copyright. All rights reserved.

AB - Abstract The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S- and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 ? 10-9 and P = 3.19 ? 10-12). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34% per variant allele copy; P = 8.15 ? 10-8). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single nucleotide variations (SNVs) may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity. This article is protected by copyright. All rights reserved.

KW - fluvastatin

KW - CYP2C9

KW - SLCO1B1

KW - pharmacokinetics

KW - pharmacogenomics

KW - genotype score

KW - massive parallel sequencing

KW - next generation sequencing

KW - 317 Pharmacy

U2 - 10.1002/cpt.1463

DO - 10.1002/cpt.1463

M3 - Article

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

ER -