Instantaneous input hypothesis in pharmacokinetic studies

Observed venous plasma concentrations of furosemide, propranolol, griseofulvin, and theophylline at 0.33 and 0 66 min after intravenous bolus injections to unanesthetized dogs were compared with those extrapolated using the instantaneous input hypothesis. At 0.33 min, extrapolated/observed plasma level ratios as high as 20.5, 65.5, 226, and 1.17 were found for these four drugs, respectively. Venous plasma levels peaked at 1 min postinjection in all studies. Total plasma areas (AUC₀)- estimated using the instantaneous input principle were higher by as much as 6.0, 6.8, and 19.6% for propranolol, griseofulvin, and furosemide, respectively, when compared with experimental data. The effect on theophylline was negligible. These results suggest the need for cautious interpretation of some venous pharmacokinetic data. More studies in animals and humans are required to assess the magnitude of deviation from the instantaneous input hypothesis for drugs in general.