A computer simulation of the food effect: transient changes in hepatic blood flow and Michaelis-Menten parameters as mediators of hepatic first pass metabolism and bioavailability of propranolol.
A physiological model of propranolol disposition was designed to help explain the large increase in AUC seen when the drug is administered with food. The mass balance equation for the liver compartment used Michaelis-Menten terms to describe hepatic metabolism. Previously published pharmacokinetic and physiological parameters were used throughout. The three parameters, Qh, Kmt, and Vmax, were varied for different durations and by a factor of two to increase AUC. The parameter variations were patterned after the changes in splanchnic blood flow following a high protein meal. The model exhibits saturation kinetics for most of the absorption phase after a simulated single oral dose of 1 mg kg-1, during which hepatic extraction is decreased. As the dose is decreased, the degree of saturation lessens. Using an input rate representative of regular release, changes to Qh caused little change in AUC. While the model was moderately sensitive to Kmt changes, large increases in AUC were seen after Vmax was altered. The sensitivity of the system to Kmt and Vmax changes became greater as the duration of the changes was increased. The AUC was most sensitive to Vmax variation, leading to the conclusion that mechanisms involving this parameter should be explored further. Reducing the input rate to mimic sustained release decreased the AUC for a given dose as well as the sensitivity of AUC to changes in Kmt and Vmax.
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
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Coutts
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D000818:Animals; D001682:Biological Availability; D003198:Computer Simulation; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005502:Food; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008102:Liver Circulation / Q000502:physiology*; D008954:Models, Biological; D011433:Propranolol / Q000493:pharmacokinetics*
D011433:Propranolol