Predictions of bisphenol A hepatic clearance in the isolated perfused rat liver (IPRL): impact of albumin binding and of co-administration with naproxen

Abstract

1. This study aimed (i) to characterise hepatic clearance (CL) of bisphenol A (BPA) and naproxen (NAP) administered alone or in binary mixtures to highlight the influence of a binding to albumin (ALB) using an isolated perfused rat liver (IPRL) system; and (ii) to compare results of prediction algorithms with measured clearance rates.

2. The IPRL system and liver microsomes were used to determine the metabolic constants of BPA and NAP either in the presence or absence of ALB. In this study, the IPRL was used as proxy for the in vivo situation. Accordingly, diverse in vitro-to-in vivo and in vivo-to-in vivo extrapolations (IVIVEs) were made to predict CL of BPA determined in situ/in vivo with ALB from metabolic data determined without ALB by using different binding correction methods (i.e., direct and conventional scaling as well as a novel scaling considering an ALB-facilitated uptake mechanism).

3. The addition of ALB significantly influenced the liver kinetics of BPA and NAP either administered alone or in binary mixtures, which was reflected in the Michaelis-Menten constants. Analysis of concomitant exposures of BPA and NAP gave a fully competitive inhibition. Furthermore, the IVIVE method based on the ALB-facilitated uptake mechanism provided the most accurate predictions of CL_{in vivo} as compared with the other IVIVE methods when the impact of ALB is considered.

4. Our findings support the notion that high binding to ALB reduces the biotransformation of BPA and NAP when administered alone or in mixtures in the IPRL system. However, the free drug concentration in liver in vivo is probably higher than expected since the IVIVE method based on a potential ALB-facilitated uptake mechanism is the most robust prediction method. Overall, this study should improve the physiologically-based pharmacokinetic (PBPK) modelling of chemical–drug interactions.

Keywords:

• Isolated perfused rat liver
• in vitro–in vivo extrapolations
• hepatic clearance
• bisphenol A
• naproxen
• albumin
• interactions
• clearance modelling

Declaration of interest

The authors declare that there are no conflicts of interest.