RT Journal Article
SR Electronic
T1 Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1875
OP 1882
DO 10.1124/dmd.113.052753
VO 41
IS 10
A1 Tsuyoshi Takahashi
A1 Tatsuyuki Ohtsuka
A1 Takahiro Yoshikawa
A1 Ichiro Tatekawa
A1 Yasuhiro Uno
A1 Masahiro Utoh
A1 Hiroshi Yamazaki
A1 Toshiyuki Kume
YR 2013
UL http://dmd.aspetjournals.org/content/41/10/1875.abstract
AB Drug–drug interactions (DDIs) caused by the inhibition of hepatic uptake transporters such as organic anion transporting polypeptide (OATP) can affect therapeutic efficacy and cause adverse reactions. We investigated the potential utility of pitavastatin as an in vivo probe substrate for preclinically studying OATP-mediated DDIs using cynomolgus monkeys. Cyclosporine A (CsA) and rifampicin (RIF), typical OATP inhibitors, inhibited active uptake of pitavastatin into monkey hepatocytes with half-maximal inhibitory concentration values comparable with those in human hepatocytes. CsA and RIF increased the area under the plasma concentration–time curve (AUC) of intravenously administered pitavastatin in cynomolgus monkeys by 3.2- and 3.6-fold, respectively. In addition, there was no apparent prolongation of the elimination half-life of pitavastatin due to the decrease in both hepatic clearance and volume of distribution. These findings suggest that DDIs were caused by the inhibition of hepatic uptake of pitavastatin. CsA and RIF increased the AUC of orally administered pitavastatin by 10.6- and 14.8-fold, respectively, which was additionally caused by the effect of the CsA and RIF in the gastrointestinal tract. Hepatic contribution to the overall DDI for oral pitavastatin with CsA was calculated from the changes in hepatic availability and clearance, and it was shown that the magnitude of hepatic DDI was comparable between the present study and the clinical study. In conclusion, pharmacokinetic studies using pitavastatin as a probe in combination with drug candidates in cynomolgus monkeys are useful to support the assessment of potential clinical DDIs involving hepatic uptake transporters.