Prediction of the Possibility of the Secondary Peaks of iv Bolus Drug Plasma Concentration Time Curve by the Model That Directly Takes into Account the Transit Time Through the Organ

The article considers the problem of determination of organ clearance and the time course of drug plasma concentration using the model for which the drug transit time through the organ is regarded as one of the parameters. The suggested nonsteady state approach to the determination of organ clearance conceptually corresponds to the parallel tube model, and directly takes into account the delay of drug exit from the organ due to the transit time tau. The considered model is linear, so that the definition of mean organ clearance as D(o)/AUC, where D(o) is the quantity of drug eliminated by the organ and AUC is the area under drug plasma concentration time curve, is relevant and yields the same value as obtained at steady state. The plasma concentration-time profile for a two-compartmental model (blood-organ) with the account of transit time T is found. It is a piece-continuous function, which includes exponential and polynomial terms. The considered model provides a better understanding in which situation the account of transit time through the organ may influence pharmacokinetic profiles. The unique feature of the model is that it predicts the possibility of the oscillating drug plasma concentration-time curves following iv bolus dose due to the initial fast distribution of drug into the organs. This could explain the secondary peaks or humps of drug plasma concentration profiles sometimes observed at the early time points after iv bolus injection for compounds that do not undergo hepatic recirculation. (C) 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4376-4390, 2009