Species differences in the drug-drug interaction between atorvastatin and cyclosporine: In vivo study using a stable isotope-IV method in rats and dogs.

In this study, drug-drug interaction (DDI) between atorvastatin (ATV) and cyclosporine (CsA) was kinetically analyzed using a stable isotope-IV method in rats and dogs. Obtained results were compared with the clinical data quoted from literatures to clarify the species difference in DDI both qualitatively and quantitatively. ATV only or ATV with CsA was orally administered to rats or dogs, and at 90 minutes after administration, a small amount of deuterium labeled ATV (ATV-d5) was intravenously injected. Assuming that ATV-d5 exhibits the same pharmacokinetic (PK) profile with ATV, PK parameters for absorption and elimination of ATV were calculated. Plasma levels of orally administered ATV were significantly enhanced by co-administration of CsA both in rats, dogs and humans, resulted in 9.8, 31, and 8.7-fold increase in systemic exposure calculated as AUCpo. High intensity of the DDI in dogs was mainly attributed to the marked decrease of the intrinsic hepatic clearance (to 1/10 of the control), which was induced by the inhibition of hepatic uptake of ATV via organic anion transporting polypeptide 1B1 (OATP1B1). CsA also affected the absorption of ATV form GI tract. Absorbed fraction of ATV into portal vein (calculated as Fa*Fg) was increased almost same extent in rats and dogs (around 3.0-fold) by co-administration of CsA. Inhibition of efflux transport via breast cancer resistance protein as well as the intestinal metabolism mediated by CYP enzymes contributed to the DDI occurred in the intestinal tract. In conclusion, PK analysis on the DDI between ATV and CsA in rats and dogs clearly demonstarted the factors to cause species differences in the extent of DDI. This type of quantitative analysis of DDIs in both small and large animals can be a great help to predict the extent of DDI in humans in the clinical study.