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Application of Pharmacokinetic Modeling to Characterize Hepatobiliary Disposition of Imaging Agents and Alterations due to Liver Injury in Isolated Perfused Rat Livers

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Abstract

Background

Understanding the impact of altered hepatic uptake and/or efflux on the hepatobiliary disposition of the imaging agents [99mTc]Mebrofenin (MEB) and [153Gd]Gadobenate dimeglumine (BOPTA) is important for proper estimation of liver function.

Methods

A multi-compartmental pharmacokinetic (PK) model describing MEB and BOPTA disposition in isolated perfused rat livers (IPRLs) was developed. The PK model was simultaneously fit to MEB and BOPTA concentration-time data in the extracellular space, hepatocytes, bile canaliculi, and sinusoidal efflux in livers from healthy rats, and to BOPTA concentration-time data in rats pretreated with monocrotaline (MCT).

Results

The model adequately described MEB and BOPTA disposition in each compartment. The hepatocyte uptake clearance was much higher for MEB (55.3 mL/min) than BOPTA (6.67 mL/min), whereas the sinusoidal efflux clearance for MEB (0.000831 mL/min) was lower than BOPTA (0.0127 mL/min). The clearance from hepatocytes to bile (CLbc) for MEB (0.658 mL/min) was similar to BOPTA (0.642 mL/min) in healthy rat livers. The BOPTA CLbc was reduced in livers from MCT-pretreated rats (0.496 mL/min), while the sinusoidal efflux clearance was increased (0.0644 mL/min).

Conclusion

A PK model developed to characterize MEB and BOPTA disposition in IPRLs was used to quantify changes in the hepatobiliary disposition of BOPTA caused by MCT pretreatment of rats to induce liver toxicity. This PK model could be applied to simulate changes in the hepatobiliary disposition of these imaging agents in rats in response to altered hepatocyte uptake or efflux associated with disease, toxicity, or drug-drug interactions.

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Data Availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

WinNonlin software was generously provided to the Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, by Certara as a member of the Pharsight Academic Center of Excellence Program. This work in part, was presented at the 24th International Symposium on Microsomes and Drug Oxidations (MDO)/ 13th International Meeting of the International Society for the Study of Xenobiotics (ISSX).

Funding

This research was supported by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under Award Number R35 GM122576, and the Swiss National Foundation (Grant 310030-126030). Angela Jeong was supported by a Pharmacokinetics/Pharmacodynamics Fellowship from Allucent.

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Authors and Affiliations

  1. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 100 L Beard Hall, CB# 7569, Chapel Hill, NC, 27599-7569, USA

    Angela Jeong & Kim L. R. Brouwer

  2. Centre de recherche sur l’inflammation, Université de Paris, Inserm, U1149, CNRS, ERL8252, F-75006, Paris, France

    Catherine M. Pastor

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  1. Angela Jeong
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Correspondence to Kim L. R. Brouwer.

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Jeong, A., Pastor, C.M. & Brouwer, K.L.R. Application of Pharmacokinetic Modeling to Characterize Hepatobiliary Disposition of Imaging Agents and Alterations due to Liver Injury in Isolated Perfused Rat Livers. Pharm Res 40, 2513–2523 (2023). https://doi.org/10.1007/s11095-023-03549-2

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