Our laboratory has recently described the use of mean residence time concepts to differentiate changes in first pass metabolism versus clearance for metabolic drug-drug interactions following oral dosing, for determining whether intestinal transporter drug-drug interactions are clinically relevant and for defining the importance of transporters in drug disposition. Mean residence time concepts have been previously proposed as a methodology to characterize drug metabolite pharmacokinetic characteristics and precursor-product relationships. This cannot be accomplished by dosing metabolites, which have very different lipophilicity and membrane permeability values as compared to the parent drug. Previous publications have suggested that the method will work following intravenous dosing but that for successful estmates following oral dosing one must be able to determine Fg and Fh, the fractional bioavailability resulting from intestinal and hepatic metabolism, respectively. Here we point out that the use of mean residence time concepts to characterize metabolites is based on the well-stirred model concept that all outcomes are driven by the measured systemic concentration. For most metabolic reactions the well-stirred model concept will not be valid and estimations using mean residence time concepts cannot be trusted to be accurate. Very seldom does a lipophilic drug only lead to one metabolite. For example, many phase 1 metabolites undergo phase 2 conjugation. That is, sequential metabolism, where a primary metabolite is then further metabolized within the liver, is a very common occurrence. Under such circumstances the systemic concentration of the first metabolite is not the driving force concentration for formation of the second metabolite. Thus, in conclusion, mean residence time concepts can provide useful measures of drug disposition, but in no case should they be used to characterize metabolite kinetics unless only a single metabolite is formed and then eliminated in the urine. But for such a situation, the more easily and more relevant calculation of renal clearance should be utilized to define metabolite kinetics.
Upon completion, participants will be able to derive the use of mean residence concepts to characterize drug metabolite pharmacokinetics.
Upon completion, participants will be able to describe why dosing drug metabolites will not provide useful information.
Upon completion, participants will be able to understand the limits of the methodology to characterize drug metabolite pharmacokinetics and define precusor-product outcomes.
Upon completing, participants will understand the relavance of sequential metabolism is utilizing mean residence time concepts for metabolites.