ABSTRACT
Response to statin therapy is often unpredictable because of variability in metabolism and transport. In the recently created organic anion transporting-polypeptide 1b2 (Oatp1b2/Slco1b2)-null mice, the investigators found significantly lower liver-to-plasma ratios compared with controls for atorvastatin (16.0 ± 5.1 vs 43.5 ± 13.7, P = .002) and rosuvastatin (15.2 ± 3.3 vs 28.4 ± 9.3, P = .03), but not simvastatin (5.2 ± 1.1 vs 6.3 ± 2.9, P = .49), following tail vein injection of 1 mg/kg of each drug. In addition, the investigators examined intraindividual variation in atorvastatin, rosuvastatin, and simvastatin pharmacokinetics in healthy human subjects in a crossover study design. Areas under the plasma concentration-time curve of atorvastatin and simvastatin acid were significantly related (Spearman r = 0.68; P = .035), whereas rosuvastatin profile was not related to atorvastatin or simvastatin exposure. Together, these results in mice and humans demonstrate that predictability of exposure to one statin based on another is dependent on the specific statin pairs and the context in which they are compared.
Subject(s)
Fluorobenzenes/pharmacokinetics , Heptanoic Acids/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Organic Anion Transporters, Sodium-Independent/metabolism , Pyrimidines/pharmacokinetics , Pyrroles/pharmacokinetics , Simvastatin/pharmacokinetics , Sulfonamides/pharmacokinetics , Adult , Animals , Area Under Curve , Atorvastatin , Cross-Over Studies , Female , Fluorobenzenes/blood , Heptanoic Acids/blood , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Liver/metabolism , Liver-Specific Organic Anion Transporter 1 , Male , Mice , Mice, Knockout , Middle Aged , Organic Anion Transporters, Sodium-Independent/genetics , Pyrimidines/blood , Pyrroles/blood , Rosuvastatin Calcium , Simvastatin/blood , Sulfonamides/blood , Young AdultABSTRACT
The multidrug resistance protein 4 (MRP4) is an efflux transporter involved in the transport of endogenous substrates and xenobiotics. We measured MRP4 mRNA and protein expression in human livers and found a 38- and 45-fold variability, respectively. We sequenced 2 kb of the 5'-flanking region, all exons and intron/exon boundaries of the MRP4 gene in 95 patients and identified 74 genetic variants including 10 non-synonymous variations, seven of them being located in highly conserved regions. None of the detected polymorphisms was significantly associated with changes in the MRP4 mRNA or protein expression. Immunofluorescence microscopy indicated that none of the non-synonymous variations affected the cellular localization of MRP4. However, in cholestatic patients the MRP4 mRNA and protein expression both were significantly upregulated compared to non-cholestatic livers (protein: 299+/-138 vs 100+/-60a.u., P<0.001). Taken together, human hepatic MRP4 expression is highly variable. Genetic variations were not sufficient to explain this variability. In contrast, cholestasis is one major determinant of human hepatic MRP4 expression.
