Enantiospecific Pharmacogenomics of Fluvastatin

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. CYP 2C9*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 × 10 −9 and P = 3.19 × 10 −12 ). In contrast, SLCO 1B1 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 CYP 2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO 2B1 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 CYP 2C9 and SLCO 1B1 may be useful in predicting fluvastatin efficacy and myotoxicity.