A theoretical basis has been established for the bioavailability assessment of drug and metabolite wherein the biotransformation of one to the other is reversible. The method is applicable to linear systems and requires knowledge of drug metabolite clearance rates as well as the rate of their interconversion. While not necessary, an unconventional definition of plasma clearance appears desirable and expeditious. Depending on the experimental situation, clearance values may change between treatments; these changes should be recognized and accommodated. Alterations in experimental design are discussed as means to minimize the need for assumptions and/or to provide data in suitable form as tests of internal consistency.