UCSF

Statins are one of the most commonly prescribed drug classes in the world to treat hyperlipoidemia. Statins inhibit HMG-CoA reductase to block the upstream cholesterol synthesis pathway in the liver. Seven different statins are currently on the market in the US and many exhibit differential drug exposure in different ethnic groups, including pravastatin, rosuvastatin, and simvastatin. In the rosuvastatin drug label, FDA recommends a lower starting dose for Asians due to the observation of 2 fold higher rosuvastatin systemic exposure. The mechanism of differential rosuvastatin exposure between Asians and Whites remains under investigation.

Rosuvastatin is a minimally metabolized drug and with 90% excreted unchanged. According to the Biopharmaceutics Drug Disposition Classification System, it is a class III compound, which suggests that uptake and efflux transporters are necessary for rosuvastatin disposition. Two drug transporters, OATP1B1 (SLCO1B1) and BCRP (ABCG2), are well described in the literature to play important roles in rosuvastatin absorption, distribution, and elimination. Although previous studies have shown that increase in rosuvastatin exposure was associated with either OATP1B1 or BCRP reduced function variants in both ethnicities, the two-fold higher rosuvastatin AUC in Chinese cannot be explained by either OATP1B1 or BCRP reduced function variants and their allele frequencies alone.

Therefore, we hypothesize that both OATP1B1 and BCRP reduced function variants and their allele frequencies together dictate the rosuvastatin exposure. The research presented here first evaluated the effect of the major allele of OATP1B1 and BCRP together on rosuvastatin pharmacokinetics in Asian and White healthy volunteers and showed the differential rosuvastatin exposure was mitigated after controlling for both OATP1B1 and BCRP wildtype. Secondly, we evaluated the influence of intestinal absorption on rosuvastatin pharmacokinetics. Our study showed no clinically significant increase in rosuvastatin exposure when the upper GIs are bypassed in obese patients, indicating proximal intestinal absorption might play a minimal role in rosuvastatin pharmacokinetics. Collectively, these studies aim to highlight the potential for personalized medicine of rosuvastatin dosing given the different genetic background that may translate to more effective treatment of hyperlipidemia and obese patients.