Effect of Cryopreservation on Enzyme and Transporter Activities in Suspended and Sandwich Cultured Rat Hepatocytes

The AAPS Journal
Janneke KeeminkPieter Annaert

Abstract

Freshly-isolated rat hepatocytes are commonly used as tools for hepatic drug disposition. From an ethical point of view, it is important to maximize the use of isolated hepatocytes by cryopreservation. The present study compared overall hepatocyte functionality as well as activity of the organic anion transporting polypeptide (Oatp), multidrug resistance-associated protein 2 (Mrp2), and UDP-glucuronosyltransferase 1 (Ugt1), in in vitro models established with cryopreserved and freshly-isolated hepatocytes. A similar culture time-dependent decline in cellular functionality, as assessed by urea production, was observed in sandwich-cultured hepatocytes (SCH) obtained from freshly-isolated and cryopreserved cells. Concentration-dependent uptake kinetics of the Oatp substrate sodium fluorescein in suspended hepatocytes (SH) or SCH were not significantly affected by cryopreservation. Mrp2-mediated biliary excretion of 5 (and 6)-carboxy-2',7'-dichlorofluorescein by SCH was assessed with semi-quantitative fluorescence imaging: biliary excretion index values increased between day 3 and day 4, but did not differ significantly between cryopreserved and freshly-isolated hepatocytes. Finally, telmisartan disposition was evaluated in SCH to ...Continue Reading

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Citations

Jan 22, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Paresh P ChotheNiresh Hariparsad
Aug 6, 2021·The Journal of Pharmacology and Experimental Therapeutics·Marlies OortsPieter Annaert

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Methods Mentioned

BETA
Protein assay
Fluorescence
fluorescence microscopy

Software Mentioned

Berkeley
NLS2 package
ImageJ
NONMEM® ( ICON plc )
Madonna
R

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