Physiologically based pharmacokinetic model for the renal clearance of iodopyracet and the interaction with probenecid in the dog.
Plasma kinetics and renal excretion of iodopyracet (3.0 g, administered i.v.) with and without concomitant administration of probenecid were studied in the beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by probenecid. A physiologically based kidney model is proposed comprising all the functional characteristics of the kidney that determine the excretion of iodopyracet, i.e. renal plasma flow, urine flow, protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. Renal clearance of iodopyracet is characterized by supply-limited elimination at low plasma concentrations and capacity-limited elimination at high plasma levels. The interaction with probenecid could be adequately described with the model by competitive inhibition of the carrier-mediated uptake of iodopyracet into the tubular cells. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of iodopyracet within the cells, which was clearly diminished in the presence of probenecid.
Russel
F G
FG
Department of Pharmacology, University of Nijmegen, The Netherlands.
Wouterse
A C
AC
Van Ginneken
C A
CA
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004347:Drug Interactions; D006207:Half-Life; D007468:Iodopyracet / Q000493:pharmacokinetics* / Q000652:urine; D007668:Kidney / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D011339:Probenecid / Q000494:pharmacology*; D011485:Protein Binding
D001798:Blood Proteins; D011339:Probenecid; D007468:Iodopyracet