IN-VIVO DETERMINATION OF DRUG KINETIC LINEARITY AND INDIVIDUAL ORGAN ELIMINATION BY THE ACCELERATED INFUSION TECHNIQUE

The objectives of this study were to (1) establish a controlled drug i nput method, accelerated infusion, for pharmacokinetic analysis in ani mals and (2) use the accelerated infusion method to determine the biol ogical barriers responsible for the low oral bioavailability of a pept idic compound in rats. The method involves the administration of an in fusion at flow rates which increase linearly with time, that is, accel erated infusion (AI). The accuracy of the system in delivering AIs was tested by comparing the observed volumes with the expected volumes. F or experiments with the peptidic compound, a solution was administered by AI into the systemic circulation of rats via the carotid artery (I A). The pharmacokinetic linearity of the compound was determined from the linear phase of the concentration-time curve with the systemic cle arance (CL(s)) calculated from the slope of the linear phase. Solution s of the peptidic compound were administered into the portal vein (IPV ) or the inferior vena cava (IVC) by AI to assess the hepatic and pulm onary contribution to elimination. AIs into the duodenum (ID) assessed the roles of permeability and metabolism on the absorption of the pep tidic compound across the intestinal mucosa. The system was reliable i n delivering the desired Al in vitro. The pharmacokinetics of the pept idic compound in rats was linear up to 17 mu g/ml in blood. Systemic c learance (CL(s)) of total compound in blood was calculated to be 31 ml /min/kg. Above 17 mu g/ml, drug concentrations showed an upward deviat ion from linearity, indicating loss of linearity due to saturation of elimination. Plasma concentration-time profiles for IPV, IVC, and IA i nfusions were not substantially different. Our conclusions can be summ arized as follows: (1) Accelerated infusion is a valuable, reliable ap proach that can be used to assess pharmacokinetics linearity, first-pa ss metabolism, and bioavailability. (2) The peptidic compound has a br oad, linear kinetic range in rats, and nonlinearity at high concentrat ion is due to saturation of elimination. (3) The compound has low firs t-pass elimination in the intestinal mucosa, liver, and lung. (4) The factor that determines the oral bioavailability in rats of the peptidi c compound used in this study is mucosal permeability. (C) 1997 Elsevi er Science Inc.