A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Enantiospecific Pharmacogenomics of Fluvastatin
Tekijät: Hirvensalo P, Tornio A, Neuvonen M, Kiander W, Kidron H, Paile-Hyvarinen M, Tapaninen T, Backman JT, Niemi M
Kustantaja: WILEY
Julkaisuvuosi: 2019
Journal: Clinical Pharmacology and Therapeutics
Tietokannassa oleva lehden nimi: CLINICAL PHARMACOLOGY & THERAPEUTICS
Lehden akronyymi: CLIN PHARMACOL THER
Vuosikerta: 106
Numero: 3
Aloitussivu: 668
Lopetussivu: 680
Sivujen määrä: 13
ISSN: 0009-9236
DOI: https://doi.org/10.1002/cpt.1463
Tiivistelmä
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-fluvastatin and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 x 10(-9) and P = 3.19 x 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 x 10(-8)). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single-nucleotide variations 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.
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-fluvastatin and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 x 10(-9) and P = 3.19 x 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 x 10(-8)). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single-nucleotide variations 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.
Turun yliopiston Tutkimustietojärjestelmän portaali