Lipid-lowering effect of fluvastatin in relation to cytochrome P450 2C9 variant alleles frequently distributed in the Czech population

Summary Background CYP2C9*3 allele has been reported to correlate with increased plasma concentration of fluvastatin active form in healthy volunteers. We analyzed the correlation between the CYP2C9 genotype and cholesterol-lowering effect of fluvastatin in human hypercholesterolemic patients. Material/Methods The study was prospective, without any interventions to standard procedures of hypolipidemic treatment. CYP2C9 genotype was determined by PCR–RFLP assay in 87 patients on concomitant fluvastatin therapy, in 48 patients on monotherapy, and in a control group of 254 healthy volunteers of Czech nationality. Biochemical and clinical data were collected before the initiation of fluvastatin treatment and 12 weeks later. Results The frequency of CYP2C9 alleles did not differ significantly among groups of patients and volunteers. The most frequently observed allele was CYP2C9*2. Treatment with 80 mg of fluvastatin daily of 48 patients on monotherapy for 12 weeks resulted in mean low-density lipoprotein cholesterol (LDL-C) reduction by 25%, mean serum total cholesterol (TC) reduction by 21%, and mean triglyceride (TG) reduction by 28%. The CYP2C9*1/*3 genotype was associated with a decrease in LDL-C levels (by 40.0% for CYP2C9*1/*3, but only by 22.4% for CYP2C9*1/*1), and with the reduction of TC (by 28.6% in CYP2C9*1/*3 versus 20.2% in CYP2C9*1/*1). Conclusions In hypercholesterolemic patients, LDL-C serum concentration was decreased more significantly in fluvastatin-treated subjects bearing the CYP2C9*1/*3 genotype compared to CYP2C9*1/*1 genotype. However, due to rare occurrence of some CYP genotypes, it was impossible to report a definitive positive genotype-fluvastatin effect association.

[1]  P. Neuvonen.  Drug interactions with HMG-CoA reductase inhibitors (statins): the importance of CYP enzymes, transporters and pharmacogenetics. , 2010, Current opinion in investigational drugs.

[2]  A. Rane,et al.  Roles of different CYP enzymes in the formation of specific fluvastatin metabolites by human liver microsomes. , 2009, Basic & clinical pharmacology & toxicology.

[3]  P. Giral,et al.  Association between a frequent allele of the gene encoding OATP1B1 and enhanced LDL-lowering response to fluvastatin therapy. , 2008, Pharmacogenomics.

[4]  Harlan M Krumholz,et al.  Withdrawn: P68 , 2006 .

[5]  L. Kleinberg,et al.  The association of common SNPs and haplotypes in the CETP and MDR1 genes with lipids response to fluvastatin in familial hypercholesterolemia. , 2006, Atherosclerosis.

[6]  D. Keppler,et al.  Human Hepatobiliary Transport of Organic Anions Analyzed by Quadruple-Transfected Cells , 2005, Molecular Pharmacology.

[7]  A. Åsberg,et al.  Fluvastatin and fluvastatin extended release: a clinical and safety profile , 2004, Expert review of cardiovascular therapy.

[8]  T. Strandberg,et al.  Lipid-lowering response to statins is affected by CYP3A5 polymorphism. , 2004, Pharmacogenetics.

[9]  A. Caputi,et al.  Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. , 2004, Pharmacological research.

[10]  U. Schwarz,et al.  Clinical relevance of genetic polymorphisms in the human CYP2C9 gene , 2003, European journal of clinical investigation.

[11]  Christian Meisel,et al.  Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol‐lowering activity of (−)‐3s,5r‐fluvastatin and (+)‐3r,5s‐fluvastatin in healthy volunteers , 2003, Clinical pharmacology and therapeutics.

[12]  N. Božina,et al.  Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population. , 2003, Croatian medical journal.

[13]  J. Brockmöller,et al.  Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population , 2003, European Journal of Clinical Pharmacology.

[14]  V. Barbu,et al.  Frequency of cytochrome P450 2C9 allelic variants in the Chinese and French populations , 2003, Fundamental & clinical pharmacology.

[15]  R. Berecz,et al.  CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers , 2003, European Journal of Clinical Pharmacology.

[16]  P. Anzenbacher,et al.  Cytochromes P450 and experimental models of drug metabolism , 2002, Journal of cellular and molecular medicine.

[17]  M. Ingelman-Sundberg,et al.  Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. , 2001, British journal of clinical pharmacology.

[18]  J. Goldstein,et al.  Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. , 2001, British journal of clinical pharmacology.

[19]  A. Peyer,et al.  HMG‐CoA reductase inhibitors and P‐glycoprotein modulation , 2001, British journal of pharmacology.

[20]  J. Brockmöller,et al.  Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. , 1999, British journal of clinical pharmacology.

[21]  M. Ingelman-Sundberg,et al.  Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. , 1999, Biochemical and biophysical research communications.

[22]  H. Lennernäs,et al.  Concentration‐ and Region‐dependent Intestinal Permeability of Fluvastatin in the Rat , 1998, The Journal of pharmacy and pharmacology.

[23]  M H Tarbit,et al.  Genetic analysis of the human cytochrome P450 CYP2C9 locus. , 1996, Pharmacogenetics.

[24]  J. König.  Uptake transporters of the human OATP family: molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms. , 2011, Handbook of experimental pharmacology.

[25]  C. Scripture,et al.  Clinical Pharmacokinetics of Fluvastatin , 2001, Clinical pharmacokinetics.