Generation of cynomolgus monkey airway, liver ductal, and kidney organoids with pharmacokinetic functions

Abstract

Over the past decades, the pre-clinical evaluation of new drugs requires toxicological screening in animal models. The development of non-animal and nonclinical screening models could potentially play a role in the prediction of human pharmacokinetics of new drug candidates. In this study, we established stable organoids of the cynomolgus monkey airway, liver ductal, and kidney that could be passaged and cryopreserved. Drug sensitivity analyses revealed that very low doses of gemcitabine and 5-fluorouridine were toxic to the airway, liver ductal, and kidney organoids. Only high doses of regorafenib were toxic to liver ductal organoids while airway organoids were resistant to all doses of pemetrexed. These organoids showed tissue-specific expression of drug-metabolizing enzymes and drug transporter genes with liver ductal organoids exhibiting the most significant expression of all drug-metabolizing enzymes and transporters. The systematic evaluation of the pharmacokinetic functions of the cynomolgus monkey kidney, liver ductal, and airway organoids could find application in the pre-clinical toxicological studies of new drugs.