Abstract

The application of the Integrated Discrete Multiple Organ Co-culture (IdMOC) system in the evaluation of organ-specific toxicity is reviewed. In vitro approaches to predict in vivo toxicity have met with limited success, mainly because of the complexity of in vivo toxic responses. In vivo properties that are not well-represented in vitro include organ-specific responses, multiple organ metabolism, and multiple organ interactions. The IdMOC system has been developed to address these deficiencies. The system uses a 'wells-within-a-well' concept for the co-culturing of cells or tissue slices from different organs as physically separated (discrete) entities in the small inner wells. These inner wells are nevertheless interconnected (integrated) by overlying culture medium in the large outer containing well. The IdMOC system thereby models the in vivo situation, in which multiple organs are physically separated but interconnected by the systemic circulation, permitting multiple organ interactions. The IdMOC system, with either cells or tissue slices from multiple organs, can be used to evaluate cell type-specific or organ-specific toxicity.

 

Experimental approaches for the evaluation of in vitro toxicity include the use of tissue slices (1, 2), primary cells (3–9) and cell lines (10–12). They are generally viewed as useful for initial toxicity screening and for the mechanistic evaluation of toxic effects observed in vivo. For instance, in the pharmaceutical industry, in vitro toxicity screen- ing assays are used routinely during the early phases of drug development, to help in the design of new chemical entities with an acceptable safety profile (13, 14), and in the later phases of drug development, to aid the definition of the human safety profiles of drug candidates with animal tox- icity. It is also generally recognised that, due to the complexity of in vivo biology and physiology, in vitro approaches are inadequate as definitive tools for the assessment of in vivo toxicity. For in vitro systems to be further developed as replacements for the use of animals in toxicity testing, it is necessary to understand the key in vivo parameters that are critical for the manifes- tation of toxicity, and to logically and systemati- cally develop experimental systems to model such parameters. The development of the Integrated Discrete Multiple Organ Co-culture (IdMOC ® ) system is based on our previous success with the application of in vitro hepatic systems for the evaluation of drug metabolism and drug–drug interactions in drug development (15, 16). Our current experience with the IdMOC system (17–19) as an in vitro model of some of the key in vivo parameters for toxicity, is described. The potential of this system to refine, reduce and replace the use of animals in toxicity evaluation will also be discussed. The Integrated Discrete Multiple Organ Co-culture (IdMOC) System We consider the following properties to be impor- tant, if in vitro experimental systems are to suc- cessfully model in vivo xenobiotic toxicity (20–24): — xenobiotic metabolism by key organs; — target cells representative of key organs; — multiple organ interactions; and — predictive endpoints. The IdMOC system (17–19) was developed as an in vitro experimental system to model these critical properties. This unique system is based on the con- cept that, in the animal or human body, there are multiple organs that are physically separated, but are interconnected by the systemic circulation. The systemic circulation permits multiple organ inter- The Use of the Integrated Discrete Multiple Organ Co- culture (IdMOC ® ) System for the Evaluation of Multiple Organ Toxicity Albert P. Li Advanced Pharmaceutical Sciences, Inc. & In Vitro ADMET Laboratories, Inc., Columbia, MD, USA Summary — The application of the Integrated Discrete Multiple Organ Co-culture (IdMOC ® ) system in the evaluation of organ-specific toxicity is reviewed. In vitro approaches to predict in vivo toxicity have met with limited success, mainly because of the complexity of in vivo toxic responses. In vivo properties that are not well-represented in vitro include organ-specific responses, multiple organ metabolism, and multiple organ interactions. The IdMOC system has been developed to address these deficiencies. The system uses a ‘wells-within-a-well’ concept for the co-culturing of cells or tissue slices from different organs as physi- cally separated (discrete) entities in the small inner wells. These inner wells are nevertheless interconnected (integrated) by overlying culture medium in the large outer containing well. The IdMOC system thereby models the in vivo situation, in which multiple organs are physically separated but interconnected by the systemic circulation, permitting multiple organ interactions. The IdMOC system, with either cells or tissue slices from multiple organs, can be used to evaluate cell type-specific or organ-specific toxicity. Key words: alternative methods, cytotoxicity screening, drug development, human drug toxicity, IdMOC, in vitro toxicity, precision-cut slices, primary cultures, tissue slices. Address for correspondence: A.P. Li, Advanced Pharmaceutical Sciences, Inc. & In Vitro ADMET Laboratories, Inc.,