Analysis of drug‐drug interactions caused by the inhibition of hepatic organic anion transporting polypeptides using a rational physiologically based pharmacokinetic model and parameters obtained from human hepatocytes
Authors: Yoshikado Takashi , Toshimoto Kota , Sugiyama Yuichi 
Published: November 2023

Purpose

Clinical studies suggest the involvement of transporters in drug–drug interactions (DDIs). Physiologically based pharmacokinetic (PBPK) models are useful for the quantitative prediction of DDIs, in which changes in the concentrations of victim and perpetrator drugs are considered. The present study aimed to construct a rational method for optimizing parameters in PBPK models to explain the clinically observed interactions between statins and cyclosporine A (CsA), primarily caused by the inhibition of hepatic organic anion transporting polypeptides (OATPs).

Methods

Concomitant administration of CsA causes a 4.6‐fold increase in the area under the plasma concentration–time curves (AUCs) for pitavastatin (PTV) and a 3.5‐fold increase for fluvastatin (FLV). Enterohepatic circulation was considered in PBPK models of PTV and FLV. Hepatic elimination of statins occurs through active uptake, passive diffusion influx or efflux at the sinusoidal membrane, biliary excretion, and hepatic metabolism. Passive diffusion influx/active uptake clearance ratios (Rdif) and hepatic unbound fractions (fh) of statins in human hepatocytes were used as fixed parameters in the model. Passive diffusion influx/efflux clearance ratios (γ) of statins were calculated, considering that statins are monoanions and affected by the membrane potential.

Results and Discussion

Parameters including hepatic intrinsic clearances and the in vivo inhibition constant (Ki,u) of CsA for OATPs were optimized by fitting to the clinical data. Similar in vivo Ki,u values were obtained for PTV and for FLV (0.01–0.02 μM), which were lower than the reported in vitro Ki,u values for the uptake of statins with the coincubation of CsA (0.16–0.82 μM), but similar to that with the preincubation of CsA (0.014–0.024 μM). Blood concentration– time profiles of PTV and FLV were simulated using a model including the inhibition of breast cancer resistance protein (BCRP)‐and multidrug resistance‐associated protein 2 (MRP2)‐mediated biliary excretion in addition to the inhibition of the hepatic uptake. Although the inhibition of the biliary excretion with in vitro Ki,u values against BCRP (1.5 μM) and MRP2 (9.3 μM) slightly affected the blood concentration‐time profiles of PTV and FLV, the hepatic concentration was increased by up to 30%.

Conclusion

A rational method for the quantitative prediction of hepatic uptake transporter‐mediated DDIs was proposed. Because many OATP substrates are also recognized by biliary efflux transporters and CYPs, a methodology for predicting complicated DDIs involving hepatic uptake, biliary excretion, and metabolic processes needs to be established by increasing the accuracy of parameters obtained from in vitro experiments and improving in vitro–in vivo extrapolation based on both top‐down and bottom‐up approaches.

Support or Funding Information

This work was financially supported by a Grant‐in‐Aid for Scientific Research (S) from the Ministry of Education, Culture, Sports, Sciences, and Technology, Japan.