ABCG2421/34Compound Polymorphisms Markedly Affect The Pharmacokinetics Of Rosuvastatin

Hyperlipidemia refers to the abnormal fat metabolism in body, which could cause the values of one or more kinds of lipids higher than the normal value, thereby directly or indirectly endanger human’s health. Hyperlipidemia has been paid much attention in clinic, because this disease is a risk factor for coronary heart disease, stroke, diabetes and fatty liver. Rosuvastatin is the most commonly used drug to treat hyperlipidemia. Rosuvastatin calcium is a kind of hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which is widely used in the clinical treatment of hyperlipidemia, cerebral infarction, myocardial infarction and other diseases. Adverse drug reactions of rosuvastatin have been reported, including cases of serious kidney damager, habdomyolysis and so on. FDA confirmed that these adverse drug reactions were more likely to occur in Asian population.Breast cancer resistance protein (BCRP), which encoded by ABCG2, is the main efflux transporter of rosuvastatin. Previous studies have showed that a common polymorphism of ABCG2in Asian populations:42C>A, could significantly increase the concentration of rosuvastatin. However, the impact of another highly frequent polymorphism in Asian population (34G>A) is rarely reported. Our study examined the relationship between ABCG234G>A and the concentration of rosuvastatin. Because both ABCG2421C>A and34G>A have a high frequency in Chinese and there is no linkage disequilibrium between them, we also determined whether ABCG2421/34compound polymoiphisms would affect the pharmacokinetics of rosuvastatin. ABCG2421CA/34GA compound polymorphisms can be divided into two types according to their position on chromosomes, we named them ABCG2421CA/34GA-cis and ABCG2421CA/34GA-trans. Our study also explored the effects of these two types on the pharmacokinetics of rosuvastatin. The experiments in our study are as follow:1. We established a method of pyrosequencing of SLCO1B1 521T>C, ABCG2421C>A and34G>A, then genotyped800Chinese healthy male volunteers by this method.2. We established a reverse-PCR method to detect the two different compound polymorphisms types of ABCG2421CA/34GA in16volunteers who participateed in our pharmacokinetic experiment of rosuvastatin.3. We analyzed the relationship between ABCG2421/34compound polymorphisms and the concentration of rosuvastatin by the pharmacokinetic experiment in62Chinese male volunteers.The results showed that we successfully established the methods to detect the SNPs of SLCO1B1, ABCG2and we also established a method to detect the two different types of ABCG2421/34compound polymorphisms. Pharmacokinetic research showed that34G>A of ABCG2could significantly up-regulate the concentration of rosuvastatin. The ABCG2421/34compound polymorphisms may also affect the pharmacokinetics of rosuvastatin.Our results indicate that ABCG2421/34haplotype will significantly affect the concentration of rosuvastatin. This finding may provide a basis for the individualized treatment of rosuvastatin.