Abstract
Background
Rosuvastatin is taken up into the liver cell predominantly by organic anion-transporting polypeptide 1B1 (OATP1B1), and is also a substrate of breast cancer resistance protein (BCRP). The present study was conducted to observe whether the genetic polymorphisms of OATP1B1 and BCRP influenced the pharmacokinetics (PKs)/pharmacodynamics (PDs) of rosuvastatin in the healthy young and elderly subjects.
Methods
Open-label, one-sequence, and multiple-dose studies were conducted. Both the young and elderly subjects received 20 mg of rosuvastatin once daily for 21 days. Blood samples for PK analysis were collected before the last dose on day 21 and up to 24 hours. Blood samples for PD were collected before and after the 3-week treatment to examine the changes in lipid levels. The existence of single nucleotide polymorphisms (SNPs) of SLCO1B1 (521C>T, 388A>G, and -11187G>A) and ABCG2 (421C>A) was screened by genotyping. Plasma concentrations of rosuvastatin were determined by using LC-MS/MS. The PK parameters were calculated using a noncompartmental method.
Results
A total of 32 young and 20 elderly subjects completed the study. Maximum observed concentration (Cmax,ss) and the area under the concentration-time curve from 0 to the dosing interval at steady-state (AUCtau,ss) for rosuvastatin increased with BCRP variants in both young and elderly subjects. The mean AUCtau,ss were increased 1.47-fold (P=0.001) in the young with BCRP intermediate function (IF), and 1.35- and 1.59-fold (P>0.05) in the elderly with BCRP IF and low function (LF) group. Time to reach Cmax,ss was 5 hours in the elderly compared to that of 4 hours in the young (P=0.0265). Lipids lowering effect tended to be greater with BCRP variants but was not statistically significant in both young and elderly subjects. Compared to the elderly, the area under the %change from the baseline-time curve of LDL-c and HDL-c increased 1.24-(P=0.0107) and 2.30-fold (P=0.0314) in the young, respectively.
Conclusion
Our results suggest that both BCRP and OATP1B1 variants had a tendency to increase exposure, but only BCRP variants had a tendency to increase lipids lowering effects, which need further studies to confirm.
