Uridine 5′-Diphospho-glucuronosyltransferase 1A3 (UGT1A3) Prediction of Hepatic Clearance of Organic Anion Transporting Polypeptide 1B3 (OATP1B3) Substrate Telmisartan by Glucuronidation Using In Vitro–In Vivo Extrapolation (IVIVE)

Background and Objective

The prediction of pharmacokinetic parameters for drugs metabolised by cytochrome P450 enzymes has been the subject of active research for many years, while the application of in vitro–in vivo extrapolation (IVIVE) techniques for non-cytochrome P450 enzymes has not been thoroughly evaluated. There is still no established quantitative method for predicting hepatic clearance of drugs metabolised by uridine 5′-diphospho-glucuronosyltransferases (UGTs), not to mention those which undergo hepatic uptake. The objective of the study was to predict the human hepatic clearance for telmisartan based on in vitro metabolic stability and hepatic uptake results.

Methods

Telmisartan was examined in liver systems, allowing to estimate intrinsic clearance (CL_{int, in vitro}) based on the substrate disappearance rate with the use of liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Obtained CL_{int, in vitro} values were corrected for corresponding unbound fractions. Prediction of human hepatic clearance was made from scaled unbound CL_{int, in vitro} data with the use of the well-stirred model, and finally referenced to the literature value of observed clearance in humans, allowing determination of the essential scaling factors.

Results

The in vitro scaled CL_{int, in vitro} by UGT1A3 was assessed using three systems, human hepatocytes, liver microsomes, and recombinant enzymes. Obtained values were scaled and hepatic metabolism clearance was predicted, resulting in significant clearance underprediction. Utilization of the extended clearance concept (ECC) and hepatic uptake improved prediction of hepatic metabolism clearance. The scaling factors for hepatocytes, assessing the in vitro–in vivo difference, changed from sixfold difference to only twofold difference with the application of the ECC.

Conclusions

The study showed that taking into consideration hepatic uptake of a drug allows us to obtain satisfactory scaling factors, hence enabling the prediction of in vivo hepatic glucuronidation from in vitro data.