Impact of CYP2D6 polymorphisms on the pharmacokinetics of lovastatin in Chinese subjects.

PURPOSE: Although CYP3A4/5 enzymes play the predominant role in the metabolism of simvastatin and lovastatin, polymorphisms in CYP2D6 were reported to be associated with the cholesterol-lowering effect and/or tolerability of simvastatin. This study was performed to examine whether common CYP2D6 polymorphisms affect the pharmacokinetics of lovastatin, which is taken as the inactive prodrug lovastatin lactone and converted to active lovastatin acid. METHODS: A single-dose pharmacokinetic study was performed with lovastatin in 23 Chinese healthy male subjects. Plasma concentrations of lovastatin lactone and acid were determined by an LC-MS-MS method in samples collected over 24 h after single oral doses of 40-mg lovastatin. RESULTS: Compared with the CYP2D6 wt/wt group, the area under the plasma concentration-time curve (AUC(0-∞)) values for lovastatin lactone increased (P < 0.01) by average ratios (95% CI) of 1.57 (1.01-2.45), 2.11 (1.36-3.29), 2.52 (1.47-4.32), and 5.84 (3.16-10.78) in the wt/*10, *10/*10, *10/*5, and *5/*5 groups, and the values of lovastatin lactone plasma clearance (CL/F) were reduced on average (95% CI) by 40.4% (10.2-60.5%), 53.1% (29.3-68.9%), 63.8% (40.2-78.1%) and 84.2% (72.1-91.1%) in these genotype groups respectively. The pharmacokinetics of lovastatin acid did not differ among the genotype groups. CONCLUSION: This study demonstrates that CYP2D6 polymorphisms appeared to influence the disposition of lovastatin lactone in these subjects.

Effects of grapefruit juice and SLCO1B1 388A>G polymorphism on the pharmacokinetics of pitavastatin.

Pitavastatin undergoes little hepatic metabolism but it is a substrate for uptake and efflux transporters, particularly OATP1B1 (gene SLCO1B1). A previous study in 8 Japanese healthy subjects showed that co-administration with grapefruit juice (GFJ) resulted in a small increase in systemic exposure to pitavastatin. We examined whether common polymorphisms in SLCO1B1 might influence the pharmacokinetics of pitavastatin or the interaction with GFJ. Twelve Chinese healthy male volunteers took pitavastatin 2 mg orally with water or with GFJ on separate occasions and plasma concentrations of pitavastatin acid and lactone were measured over 48 h. GFJ increased the mean area under the plasma concentration-time curve (AUC0-48 h) for both pitavastatin acid and lactone by 14% (p<0.05). Subjects with SLCO1B1 *1b/*1b haplotype (388GG-521TT) had 47% and 44% higher systemic exposure for pitavastatin acid and lactone than the SLCO1B1 *1a carriers (388AA/AG-521TT, p<0.05 and p=0.005, respectively). The SLCO1B1 388A>G polymorphism, which increases transporter activity for some statins, was associated with higher plasma levels of pitavastatin acid and lactone in subjects with the homozygous variant indicating decreased hepatic uptake. Co-administration of pitavastatin with GFJ resulted in a small but significant increase in plasma levels in healthy Chinese subjects.

Polymorphisms in apolipoprotein E and apolipoprotein A-V do not influence the lipid response to rosuvastatin but are associated with baseline lipid levels in Chinese patients with hyperlipidemia.

BACKGROUND: Apolipoprotein E (APOE) and APOA5 play an important role in lipid transport and metabolism. Polymorphisms in APOE and APOA5 have been reported to be associated with baseline lipid levels and lipid responses to statins in different populations. OBJECTIVE: This study evaluated associations of APOE and APOA5 genotype with baseline lipid levels and response to rosuvastatin in Chinese patients with hyperlipidemia. METHODS: A total of 386 patients with hyperlipidemia, including 166 with familial hypercholesterolemia (FH), with good adherence to rosuvastatin 10 mg daily, were genotyped for the APOE e2/e3/e4 and APOA5 -1131T>C polymorphisms. The lipid profile was examined before and after at least 4 weeks of therapy. RESULTS: In patients without FH, there was a trend that e2 carriers had lower and those e4 carriers had higher low-density lipoprotein cholesterol (LDL-C) levels than subjects with the e3/e3 genotype (P > .05). However, an opposite significant association between APOE polymorphisms and LDL-C levels was observed in patients with FH (P = .005). The APOA5 -1131C variant allele was associated with increased baseline triglycerides levels in both patients with and without FH (P < .005 for both). Neither APOE nor APOA5 polymorphisms showed a significant effect on the lipid responses to rosuvastatin. CONCLUSIONS: This study demonstrates different associations of APOE polymorphisms with baseline LDL-C concentrations in Chinese patients with or without FH and confirms the strong relation between the APOA5 polymorphism and baseline triglyceride levels. These findings expand our knowledge on the genetic determinants of lipids and lipid response to rosuvastatin in Chinese patients with hyperlipidemia.