A general model of metabolite kinetics following intravenous and oral administration of the parent drug

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Abstract
A model of metabolite pharmacokinetics is developed in terms of residence time distributions and derived non‐compartmental measures. It provides quantitative insight into factors determining the concentration‐time curve of metabolite following intravenous and oral administration of the precursor drug. The AUCs and higher curve moments (mean residence times and relative dispersions) are calculated/ predicted and their dependence on mean absorption time, fraction of first‐pass metabolism and intrinsic disposition residence times of the parent drug and metabolite, respectively, is discussed. An AUC‐based method for the determination of the first‐pass effect is proposed which is not influenced by drug absorption. The approach is valid for linear pharmacokinetic systems exhibiting hepatic and renal elimination of the precursor drug; it is not restricted to specific compartmental models. Limitations of previous concepts of metabolite kinetics are defined. Criteria are presented for the appearance of concave metabolite curves in a semi‐logarithmic scale.