SLCO1B1 polymorphisms affect atorvastatin pharmacokinetics and cholesterol-lowering effects in patients with hypercholesterolemia in a microdosing approach

Background: Atorvastatin is taken up into hepatocytes via organic anion transporting polypeptide (OATP). SLCO1B1 (encoding OATP1B1) 521T>C polymorphism has been reported to increase significantly its plasma AUC of in healthy volunteers. However, effects of SLCO1B1*15 (388A>G and 521T>C) on its pharmacokinetics and cholesterol-lowering effects in patients with hypercholesterolemia remain to be investigated. A microdosing approach can avoid the unexpected high concentrations of drugs in certain populations during pharmacogenetic or drug interaction studies. Therefore, we examined feasibility of clinical microdosing pharmacogenetic study in real clinical settings. Methods: Statin-naive patients (n=47, M/F=37/10, mean age 69yr) clinically indicated to LDL cholesterol-lowering therapy with atorvastatin were enrolled in a two-period crossover study. In the first period, microdose (100 ug) of atorvastatin was orally administered and blood was collected up to following 24 hrs. After washout for 1-2 days, therapeutic dose (10 mg) of atorvastatin was orally administered and its pharmacokinetics was monitored in the similar manner, with all concomitant medications. Results: The AUC/Dose of atorvastatin at microdose was smallerthan that at therapeutic dose (204±139 vs. 445±210 pg·hr/ml/100 ug), suggesting the saturation of efflux transporters. The plasma concentration of atorvastatin in subjects with SLCO1B1*15 was significantly greater both at microdose and therapeutic dose (+73% and +80%, p<0.05), which was associated with smaller %LDL-cholesterol lowering after 6 months (-33% and -25%, p<0.1). Conclusions: In real clinical settings, microdosing pharmacogenetic study appears to be feasible and could predict plasma AUC of atorvastatin at a therapeutic dose and the magnitude of LDL-cholesterol lowering in hypercholesterolemic subjects with SLCO1B1*15.