CYP3A5*3 and SLCO1B1 c.521T>C Polymorphisms Influence the Pharmacokinetics of Atorvastatin and 2-Hydroxy Atorvastatin

Abstract

There is a large variability in individual responses to atorvastatin administration. This study assessed the pharmacogenetic effects of solute carrier organic anion transporter family member 1B1 (SLCO1B1, c.388A>G and c.521T>C) and cytochrome P450 3A5 (CYP3A5, CYP3A5*3) genetic polymorphisms on the pharmacokinetics of atorvastatin and its active metabolite, 2-hydroxy (2-OH) atorvastatin, in 46 individuals who were administered a clinically used single oral dosage of 80 mg. The Cmax and AUC of atorvastatin in CYP3A5*3/*3 carriers were 2.6- and 2.8-fold higher, respectively, than those in CYP3A5*1/*1 carriers, and similar results were observed for 2-OH atorvastatin pharmacokinetics. SLCO1B1 c.521T>C also increased the AUC of atorvastatin and 2-OH atorvastatin. The AUC ratio of atorvastatin and 2-OH atorvastatin were not affected by SLCO1B1 c.388A>G or c.521T>C, whereas CYP3A5*3 reduced the AUC ratio. In an analysis evaluating the simultaneous effect of the SLCO1B1 c.521T>C and CYP3A5*3 polymorphisms, SLCO1B1 c.521TT/CYP3A5*1/*1 carriers showed lower Cmax and AUC values for atorvastatin and 2-OH atorvastatin than in individuals with the SLCO1B1 c.521T>C and/or CYP3A5*3 genotypes. Among the participants with the SLCO1B1 c.521TT genotype, the CYP3A5*3 carriers had a higher systemic exposure to atorvastatin and 2-OH atorvastatin than the CYP3A5*1/*1 carriers. Thus, SLCO1B1 c.521T>C and CYP3A5*3 polymorphisms affect the pharmacokinetics of atorvastatin and 2-OH atorvastatin.

The Chinese-Han Population Carrying Wild-type Genotypes of SLCO1B1 388A>G, SLCO1B1 521T>C, CYP3A4 1B, CYP3A4 1G, and CYP3A5*3 Exhibits a Significant Alteration in the Pharmacokinetics of Atorvastatin Calcium

“…By lowering levels of low-density lipoprotein-bound cholesterol, AC can reduce the risk of atherosclerosis. The efficacy and safety of AC in facilitating the primary and secondary prevention of cardiovascular events have been demonstrated in various clinical trials [1][2][3]. However, due to the diverse genetic characteristics of metabolism and high drug plasma exposure, individual differences exist in clinical efficacy and adverse events, especially statin-induced myopathy [4,5].…”

“…Once ingested, several enzymes and transporters participate in its metabolism and transport in vivo. Until recently, drugmetabolizing enzymes, such as cytochrome P450 enzymes (CYPs), were considered the major determinants of statin disposition [3,[9][10][11]. Among these enzymes, those encoded by CYP3A4 and CYP3A5 are particularly important [12,13].…”

“…Data from in vitro studies have reported that CYP3A4 and CYP3A5 were responsible for 85% and 15% of atorvastatin metabolism, respectively [8,14]. AC is first transformed into its lactone form and subsequently into two pharmacologically active metabolites (2-hydroxyatorvastatin and 4-hydroxy-atorvastatin) by these enzymes [3,15]. Aside from metabolic enzymes, AC also heavily rely on drug transporter proteins for its disposition and efficacy [3,6].…”

“…AC is first transformed into its lactone form and subsequently into two pharmacologically active metabolites (2-hydroxyatorvastatin and 4-hydroxy-atorvastatin) by these enzymes [3,15]. Aside from metabolic enzymes, AC also heavily rely on drug transporter proteins for its disposition and efficacy [3,6]. For instance, organic anion-transporting polypeptides and efflux transporter such as OATP 1B1, ABCB1, and ABCG2 are thought to play key roles in transporting statins into hepatocytes [6,8,14,16].…”

“…Two common genetic variations in SLCO1B1 (the encoding gene of OATP 1B1), 388A ＞ G (rs2306283) and 521T ＞ C(rs4149056), can interfere with the localization of the transporter to the plasma membrane, leading to higher systemic statin concentrations [3,6,8,16]. SLCO1B1 521T ＞ C (rs4149056) has been shown to interfere with the localization of the transporter to the plasma membrane, leading to decreased liver uptake and greater systemic statin concentrations, thereby resulting in increased muscle statin exposure responsible for statin-related myotoxicity [3,6,8,20]. On the other hand, the SLCO1B1 388A＞G(rs2306283) polymorphism has demonstrated a trend toward lower plasma statin levels in some healthy volunteer studies, although this association is not always observed [3,21].…”