The effect of SLCO1B1*15 on the disposition of pravastatin and pitavastatin is substrate dependent: the contribution of transporting activity changes by SLCO1B1*15.

OBJECTIVE

This study was addressed to understand the underlying mechanism of the substrate-dependent effect of genetic variation in SLCO1B1, which encodes OATP1B1 (organic anion transporting polypeptide) transporter, on the disposition of two OATP1B1 substrates, pravastatin and pitavastatin, in relation to their transport activities.

METHODS

The uptake of pravastatin, pitavastatin, and fluvastatin was measured in oocytes overexpressing SLCO1B11a and SLCO1B115 to compare the alterations of in-vitro transporting activity. After 40-mg pravastatin or 4-mg pitavastatin was administered to 11 healthy volunteers with homozygous genotypes of SLCO1B1*1a/1a and SLCO1B115/15, the pharmacokinetic parameters of pravastatin and pitavastatin were compared among participants with SLCO1B11a/1a and SLCO1B115/*15 genotypes.

RESULTS

The uptake of pravastatin and pitavastatin in SLCO1B115 overexpressing oocytes was decreased compared with that in SLCO1B115, but no change occurred with fluvastatin. The fold change of in-vitro intrinsic clearance (Clint) for pitavastatin in SLCO1B115 compared with SLCO1B11a was larger than that of pravastatin (P<0.0001). The clearance (Cl/F) of pitavastatin was decreased to a greater degree in participant with SLCO1B115/15 compared with that of pravastatin in vivo (P<0.01), consistent with in-vitro study. As a result, Cmax and area under the plasma concentration-time curve of these nonmetabolized substrates were increased by SLCO1B115 variant. The greater decrease in the transport activity for pitavastatin in SLCO1B115 variant compared with SLCO1B1*1a was, however, associated with the greater effect on the pharmacokinetics of pitavastatin compared with pravastatin in relation to the SLCO1B1 genetic polymorphism.

CONCLUSION

This study suggests that substrate dependency in the consequences of the SLCO1B1*15 variant could modulate the effect of SLCO1B1 polymorphism on the disposition of pitavastatin and pravastatin.