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

Abstract

ABSTRACT: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 K i values (1.5, 9.1, and 4.0 M, 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.

Hepatic Uptake in the Dog: Comparison of Uptake in Hepatocytes and Human Embryonic Kidney Cells Expressing Dog Organic Anion-Transporting Polypeptide 1B4

“…A good correlation between the predicted hepatic clearances of OATP substrates, estimated using an in vitro uptake assay with hepatocytes, and observed hepatic clearances has been well characterized Watanabe et al, 2009Watanabe et al, , 2010Watanabe et al, , 2011. Thus, OATP transporters are thought to play crucial roles as determinants of hepatic clearance of transporter substrates.…”

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

“…This is also implied in humans by a one-to-one correlation between in vivo non-renal clearances of 9 OATP substrates in humans and the predicted clearances from in vitro uptake assay with human cryopreserved hepatocytes. 19) Regarding statins, Watanabe et al have demonstrated that the overall hepatic clearance of 4 statins, pitavastatin, rosuvastatin, atorvastatin and fluvastatin is mainly dominated by the hepatic uptake process. 20) Pitavastatin and rosuvastatin are not metabolized in rats and mainly excreted into bile in an unchanged form, whereas atorvastatin and fluvastatin, which are both reported to be OATP substrates, are extensively metabolized by CYP3A4 and CYP2C9, respectively.…”

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

“…Kidney slices can be used to investigate drug uptake at the basolateral membrane but not tubular reabsorption (37,38). An advantage of kidney slices is that the interactions of multiple substrates, inhibitors and endogenous transporters can be investigated in this complex system (38).…”

“…An advantage of kidney slices is that the interactions of multiple substrates, inhibitors and endogenous transporters can be investigated in this complex system (38). Imaging technology (e.g.…”

“…The uptake of drugs in kidney slices can be affected by inter-batch and/or inter-individual variability (37), which must be considered for any IVIVE strategy, e.g. by normalising data against the relative activity/content of a marker in each kidney slice batch (38). The IVIVE of transporter kinetic data generated in this complex in vitro system is performed by kidney weight (Table III).…”