Impact of OATP1B1, MDR1, and CYP3A4 expression in liver and intestine on interpatient pharmacokinetic variability of atorvastatin in obese subjects

• Published in: Clinical pharmacology and therapeutics Vol. 93; no. 3; p. 275
• Main Authors: Ulvestad, M, Skottheim, I B, Jakobsen, G S, Bremer, S, Molden, E, Asberg, A, Hjelmesæth, J, Andersson, T B, Sandbu, R, Christensen, H
• Format: Journal Article
• Language: English
• Published: United States 01.03.2013
• Subjects: Adult; Atorvastatin; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 - analysis; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - physiology; Body Mass Index; Cytochrome P-450 CYP3A - analysis; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - physiology; Female; Heptanoic Acids - pharmacokinetics; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Intestinal Mucosa - metabolism; Liver - metabolism; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Obesity - metabolism; Organic Anion Transporters - analysis; Organic Anion Transporters - genetics; Organic Anion Transporters - physiology; Pyrroles - pharmacokinetics
• ISSN: 1532-6535
• DOI: 10.1038/clpt.2012.261

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.