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 input method, accelerated infusion, for pharmacokinetic analysis in animals and (2) use the accelerated infusion method to determine the biological barriers responsible for the low oral bioavailability of a peptidic compound in rats. The method involves the administration of an infusion at flow rates which increase linearly with time, that is, accelerated infusion (AI). The accuracy of the system in delivering AIs was tested by comparing the observed volumes with the expected volumes. For experiments with the peptidic compound, a solution was administered by AI into the systemic circulation of rats via the carotid artery (IA). The pharmacokinetic linearity of the compound was determined from the linear phase of the concentration-time curve with the systemic clearance (CLs) calculated from the slope of the linear phase. Solutions of the peptidic compound were administered into the portal vein (IPV) or the inferior vena cava (IVC) by AI to assess the hepatic and pulmonary contribution to elimination. AIs into the duodenum (ID) assessed the roles of permeability and metabolism on the absorption of the peptidic compound across the intestinal mucosa. The system was reliable in delivering the desired AI in vitro. The pharmacokinetics of the peptidic compound in rats was linear up to 17 micrograms/ml in blood. Systemic clearance (CLs) of total compound in blood was calculated to be 31 ml/min/kg. Above 17 micrograms/ml, drug concentrations showed an upward deviation from linearity, indicating loss of linearity due to saturation of elimination. Plasma concentration-time profiles for IPV, IVC, and IA infusions were not substantially different. Our conclusions can be summarized as follows: (1) Accelerated infusion is a valuable, reliable approach that can be used to assess pharmacokinetics linearity, first-pass metabolism, and bioavailability. (2) The peptidic compound has a broad, linear kinetic range in rats, and nonlinearity at high concentration is due to saturation of elimination. (3) The compound has low first-pass elimination in the intestinal mucosa, liver, and lung. (4) The factor that determines the oral bioavailability in rats of the peptidic compound used in this study is mucosal permeability.
Li
J
J
Department of Drug Metabolism and Pharmacokinetics, Rhone-Poulenc Rorer Central Research, Collegeville, PA 19426-0107, USA.
Dobson
G L
GL
Marietta
M P
MP
Rhodes
G R
GR
Hidalgo
I J
IJ
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D007260:Infusion Pumps; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D007408:Intestinal Absorption; D008297:Male; D008954:Models, Biological; D010455:Peptides / Q000493:pharmacokinetics*; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D010455:Peptides