Pharmacogenetics and Drug Interaction of Rosuvastatin in Chinese

A single-dose pharmacokinetic study of rosuvastatin showed that Asian subjects have been associated with a double systemic exposure compared with non-Asian subjects but such ethnic variation has not been well elucidated. Pharmacogenetic studies in healthy volunteers also revealed that genetic polymorphisms played an important role in the systemic exposure of rosuvastatin. However, the effect of genetic variation on rosuvastatin pharmacokinetics in the treated patients has not been reported. This study was, therefore, designed to examine whether the polymorphisms of various transporters and CYP isoenzymes potentially related to the rosuvastatin pharmacokinetics could influence the plasma rosuvastatin concentrations in Chinese patients. The pharmacokinetic study involved the measurement of plasma concentrations of rosuvastatin and N-desmethyl rosuvastatin in 12-hour post-dose samples. However, such 12-hour post-dose concentration of plasma rosuvastatin is typically 2-5 mug/L, and the N-desmethyl metabolite in plasma is only one-tenth compared with the parent drug. Therefore, it is necessary to develop a more sensitive method down to ng/L level for the plasma statin measurements.;Rosuvastatin is generally well tolerated, but a case of life-threatening rhabdomyolysis has been suggested to be related to the interaction between rosuvastatin and telmisartan. Therefore, another objective of this study was to examine the potential pharmacokinetic interaction between rosuvastatin and telmisartan. In addition, in vitro experiments using bidirectional transport assay were performed to investigate the involvement of ABCG2 transporter in the interaction of telmisartan with rosuvastatin pharmacokinetics. ;The key results of the study are as follows: 1. A sensitive and specific LCMS method for the quantification of plasma rosuvastatin and N-desmethyl rosuvastatin down to 0.05 and 0.02 mugL, respectively, was developed and validated.;2. The population pharmacokinetic study of rosuvastatin i. This was the first study to demonstrate a strong association of the ABCG2 421C>A polymorphism with both the plasma concentration and the lipid-lowering effect of rosuvastatin in Chinese patients with hypercholesterolemia. i. This was the first study to demonstrate a strong association of the ABCG2 421C>A polymorphism with both the plasma concentration and the lipid-lowering effect of rosuvastatin in Chinese patients with hypercholesterolemia. ii. The SLCO1B1 521T>C polymorphism was associated with an increased systemic exposure of rosuvastatin but without a significant effect on the lipid-lowering response of rosuvastatin treatment. iii. The CYP2C9 *3 polymorphism appeared to be associated with an increased ratio of plasma rosuvastatin to its N-desmethyl metabolite. iv. The plasma concentration of rosuvastatin was mildly correlated with the LDL-C response to rosuvastatin treatment.;3. The study of the interaction of telmisartan with pharmacokinetics of rosuvastatin. i. The present in vivo study confirmed that telmisartan increased the systemic exposure of rosuvastatin. It also suggested that the interaction of telmisartan with rosuvastatin pharmacokinetics might be attributed to the increased bioavailability of the statin through the inhibitory effect of telmisartan on the efflux activity of ABCG2 transporter in enterocytes and/ or the effect of telmisartan on the glucuronidation of plasma rosuvastatin acid. ii. The in vivo study supported the mechanism that telmisartan inhibited the ABCG2 activity through its PPAR-gamma effect on the PI3K/AKt/PIP3 signaling pathway. iii. The in vitro study of rosuvastatin transport supported that rosuvastatin was a substrate of ABCG2 transporter and the ABCG2 421C>A polymorphism was associated with a decreased activity of ABCG2 transporter. iv. The results of the in vitro study on the interaction of telmisartan with rosuvastatin transport supported the proposed mechanism that the in vivo interaction of telmisartan with the systemic exposure of rosuvastatin acted through the inhibition of ABCG2 transport of rosuvastatin.;Conclusion: The ABCG2 421C>A polymorphism was shown as a major genetic determinant of lipid response to rosuvastatin mediated through affecting the systemic exposure of the statin in patients receiving a stable treatment of rosuvastatin. The present study also illustrated that a commonly prescribed antihypertensive, telmisartan, significantly interacted with the pharmacokinetics of rosuvastatin. The understanding of the genetic contribution to the response of rosuvastatin therapy and the impact of potential interaction between rosuvastatin and commonly coprescribed medication may benefit the patients through optimizing the choice and dose for different individuals, via in a personalized medicine approach.