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

Abstract

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.

Role of metabolites for drugs that undergo nonlinear first-pass effect: Impact on bioequivalency assessment using single-dose simulations

“…The relationship between C max and dose in Figure 2 was similar to that observed in the reference study8 for the propranolol C max . The power curve parameters are presented in Table 2.…”

“…Parameter values from a recent referenced study8 were used for the simulations for propanolol and presented in Table 1.…”

Nonlinear Pharmacokinetics of Mibefradil in the Dog

“…It is welldocumented that, after an oral administration, the portal vein drug concentration can be an order of a magnitude higher than that of a peripheral vein. 20 This high concentration of drug entering the liver can temporarily saturate metabolic enzymes and/or tissue binding sites. Using a computer simulation, Semple et al 20 have shown that a highly extracted drug such as propranolol behaves like a low-extraction drug during absorption.…”

“…20 This high concentration of drug entering the liver can temporarily saturate metabolic enzymes and/or tissue binding sites. Using a computer simulation, Semple et al 20 have shown that a highly extracted drug such as propranolol behaves like a low-extraction drug during absorption. This phenomenon may explain why nonlinear kinetics occurs in the dog.…”

Food Increases the Bioavailability of Tolterodine but Not Effective Exposure

“…14 Indeed, a transient change in the maximal rate of metabolite formation is a likely cause of the food effect, and it has been postulated that this is mediated via hormonal responses to feeding. 28 The food effect is not caused by increased absorption since the drugs in question are completely absorbed in the fasting state and also because there is no effect on the levels of the metabolites.…”