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.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / analysis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
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Adult
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Atorvastatin
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Body Mass Index
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Cytochrome P-450 CYP3A / analysis
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Cytochrome P-450 CYP3A / genetics
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Cytochrome P-450 CYP3A / physiology*
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Female
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Heptanoic Acids / pharmacokinetics*
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
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Intestinal Mucosa / metabolism*
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Liver / metabolism*
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Liver-Specific Organic Anion Transporter 1
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Male
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Middle Aged
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Obesity / metabolism*
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Organic Anion Transporters / analysis
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Organic Anion Transporters / genetics
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Organic Anion Transporters / physiology*
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Pyrroles / pharmacokinetics*
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Heptanoic Acids
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Liver-Specific Organic Anion Transporter 1
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Organic Anion Transporters
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Pyrroles
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SLCO1B1 protein, human
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Atorvastatin
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human