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Impact of OATP1B1, MDR1, and CYP3A4 Expression in Liver and Intestine on Interpatient Pharmacokinetic Variability of Atorvastatin in Obese Subjects.


Clin Pharmacol Ther. 2012 Dec 27;


Authors: Ulvestad M, Skottheim IB, Jakobsen GS, Bremer S, Molden E, Asberg A, Hjelmesæth J, Andersson TB, Sandbu R, Christensen H


Abstract

Individual variability in expression and function of organic anion-transporting polypeptide 1B1 (OATP1B1), multidrug resistance protein 1 (MDR1), and/or cytochrome P450 3A4 (CYP3A4) may impact the clinical response of many drugs. We investigated the correlation between expression of these proteins and pharmacokinetics of atorvastatin, a substrate of all three, in 21 obese patients with paired biopsies from liver and intestinal segments. The patients were also screened for the SLCO1B1 c.521T→C variant alleles. Approximately 30% (r(2) = 0.28) of the variation in oral clearance (CL/F) of atorvastatin was explained by hepatic OATP1B1 protein expression (P = 0.041). Patients carrying the SLCO1B1 c.521C variant allele (homozygous, n = 4; heterozygous, n = 2) exhibited 45% lower CL/F of atorvastatin than the c.521TT carriers (P = 0.067). No association between hepatic and intestinal expression of MDR1 or CYP3A4 and atorvastatin pharmacokinetics was found (P > 0.149). In conclusion, this study suggests that OATP1B1 phenotype is more important than CYP3A4 and MDR1 phenotypes for the individual pharmacokinetic variability of atorvastatin.Clinical Pharmacology & Therapeutics (2013); advance online publication 30 January 2013. doi:10.1038/clpt.2012.261.

PMID: 23361102 [PubMed - as supplied by publisher]