PT  - JOURNAL ARTICLE
AU  - Watanabe, Takao
AU  - Kusuhara, Hiroyuki
AU  - Watanabe, Tomoko
AU  - Debori, Yasuyuki
AU  - Maeda, Kazuya
AU  - Kondo, Tsunenori
AU  - Nakayama, Hideki
AU  - Horita, Shigeru
AU  - Ogilvie, Brian W.
AU  - Parkinson, Andrew
AU  - Hu, Zhuohan
AU  - Sugiyama, Yuichi
TI  - Prediction of the Overall Renal Tubular Secretion and Hepatic Clearance of Anionic Drugs and a Renal Drug-Drug Interaction Involving Organic Anion Transporter 3 in Humans by In Vitro Uptake Experiments
AID  - 10.1124/dmd.110.036129
DP  - 2011 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 1031--1038
VI  - 39
IP  - 6
4099  - http://dmd.aspetjournals.org/content/39/6/1031.short
4100  - http://dmd.aspetjournals.org/content/39/6/1031.full
SO  - Drug Metab Dispos2011 Jun 01; 39
AB  - The present study investigated prediction of the overall renal tubular secretion and hepatic clearances of anionic drugs based on in vitro transport studies. The saturable uptake of eight drugs, most of which were OAT3 substrates (rosuvastatin, pravastatin, pitavastatin, valsartan, olmesartan, trichlormethiazide, p-aminohippurate, and benzylpenicillin) by freshly prepared human kidney slices underestimated the overall intrinsic clearance of the tubular secretion; therefore, a scaling factor of 10 was required for in vitro-in vivo extrapolation. We examined the effect of gemfibrozil and its metabolites, gemfibrozil glucuronide and the carboxylic metabolite, gemfibrozil M3, on pravastatin uptake by human kidney slices. The inhibition study using human kidney slices suggests that OAT3 plays a predominant role in the renal uptake of pravastatin. Comparison of unbound concentrations and Ki values (1.5, 9.1, and 4.0 μM, for gemfibrozil, gemfibrozil glucuronide, and gemfibrozil M3, respectively) suggests that the mechanism of the interaction is due mainly to inhibition by gemfibrozil and gemfibrozil glucuronide. Furthermore, extrapolation of saturable uptake by cryopreserved human hepatocytes predicts clearance comparable with the observed hepatic clearance although fluvastatin and rosuvastatin required a scaling factor of 11 and 6.9, respectively. This study suggests that in vitro uptake assays using human kidney slices and hepatocytes provide a good prediction of the overall tubular secretion and hepatic clearances of anionic drugs and renal drug-drug interactions. It is also recommended that in vitro-in vivo extrapolation be performed in animals to obtain more reliable prediction.