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English

New Pharmacokinetic Parameters of Imaging Substrates Quantified from Rat Liver Compartments

Contributors

Pastor, Catherine; Brouwer, Kim L R

Published in

Drug metabolism and disposition, vol. 50, no. 1, p. 58-64

Publication date

2022-01

First online date

2021-10-20

Abstract

Hepatobiliary imaging is increasingly used by pharmacologists to quantify liver concentrations of transporter-dependent drugs. However, liver imaging does not quantify concentrations in extracellular space, hepatocytes, and bile canaliculi. Our study compared the compartmental distribution of two hepatobiliary substrates gadobenate dimeglumine [BOPTA; 0.08 liver extraction ratio (ER)] and mebrofenin (MEB; 0.93 ER) in a model of perfused rat liver. A gamma counter placed over livers measured liver concentrations. Livers were preperfused with gadopentetate dimeglumine to measure extracellular concentrations. Concentrations coming from bile canaliculi and hepatocytes were calculated. Transporter activities were assessed by concentration ratios between compartments and pharmacokinetic parameters that describe the accumulation and decay profiles of hepatocyte concentrations. The high liver concentrations of MEB relied mainly on hepatocyte and bile canaliculi concentrations. In contrast, the three compartments contributed to the low liver concentrations obtained during BOPTA perfusion. Nonlinear regression analysis of substrate accumulation in hepatocytes revealed that cellular efflux is measurable ∼4 minutes after the start of perfusion. The hepatocyte-to-extracellular concentration ratio measured at this time point was much higher during MEB perfusion. BOPTA transport by multidrug resistance associated protein 2 induced an aquaporin-mediated water transport, whereas MEB transport did not. BOPTA clearance from hepatocytes to bile canaliculi was higher than MEB clearance. MEB did not efflux back to sinusoids, whereas BOPTA basolateral efflux contributed to the decrease in hepatocyte concentrations. In conclusion, our ex vivo model quantifies substrate compartmental distribution and transport across hepatocyte membranes and provides an additional understanding of substrate distribution in the liver. SIGNIFICANCE STATEMENT: When transporter-dependent drugs target hepatocytes, cellular concentrations are important to investigate. Low concentrations on cellular targets impair drug therapeutic effects, whereas excessive hepatocyte concentrations may induce cellular toxicity. With a gamma counter placed over rat perfused livers, we measured substrate concentrations in the extracellular space, hepatocytes, and bile canaliculi. Transport across hepatocyte membranes was calculated. The study provides an additional understanding of substrate distribution in the liver.

UNIGE affiliation entities

UNIGE research groups

Funding

  • Swiss National Science Foundation - Regulation of the hepatic transporters Oatps and Mrp2: implications for liver imaging and hepatic cholestasis

Citation (ISO format)

PASTOR, Catherine, BROUWER, Kim L R. New Pharmacokinetic Parameters of Imaging Substrates Quantified from Rat Liver Compartments. In: Drug metabolism and disposition, 2022, vol. 50, n° 1, p. 58–64. doi: 10.1124/dmd.121.000546

Main files (2)

Article (Published version)
Article (Accepted version)

Identifiers

Additional URL for this publication

https://dmd.aspetjournals.org/content/50/1/58

Journal ISSN

0090-9556
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405downloads

Technical informations

Creation

17/02/2022 12:48:00

First validation

17/02/2022 12:48:00

Update

16/03/2023 02:41:28

Status update

16/03/2023 02:41:26

Last indexation

01/11/2024 00:54:20
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