Reversible metabolism is a major phenomenon in drug disposition. Numerous compounds such as corticosteroids, estrogens, sulfonamides, N- oxides, sulfoxides, some acylglucuronide and disulfide conjugates, HMG- CoA reductase inhibitors, and many others have or are metabolites which can revert in part to the parent drug. The process may be overlooked unless the metabolite is administered directly. Other kinetic systems such as mathematically as reversible compartmental models. Methods for calculation of clearance processes for reversible metabolism or distribution have been recently extended to employ moment analysis to easily obtain steady-state volumes of distribution and residence time parameters. Conventional """"""""noncompartmental"""""""" analysis can severely distort the generation and interpretation of proper pharmacokinetic parameters. Theoretical equations and experimental systems will be developed to deal with more complex reversible models, namely (I) those exhibiting nonlinearity in one or more elements of drug metabolism or distribution, and (II) those where the drug and/or metabolite is subject to a first-pass effect.
Our specific aims i nclude: 1.) Construction of an array of theoretical model which contain one or more elements of nonlinearity (or first-pass), use of numerical integration techniques to provide serum concentration versus time patterns for drug and metabolite, and assessment of effects on calculation of distribution and elimination parameters using: a. conventional models, b. linear reversible models, and c. correct reversible models. 2.) Development of practical calculation methods to discern the correct model and provide appropriate distribution and elimination parameters for drugs and metabolites subject to reversible metabolism with some nonlinear (or first-pass) features. 3.) Evaluation of methods to discern mechanisms of drug interactions in the presence of reversible metabolism. 4.) Use of corticosteroids as both model compounds and pharmacologically relevant agents to examine the role of nonlinearities, first-year effects, and drug interactions on reversible drug disposition in the rat. Improved methods of pharmacokinetic inspection and calculation will provide more insightful characterization of the kinetics and mechanisms of drug disposition and their perturbance by drug and disease interactions when interconverting drugs and metabolites exist.