Mechanisms and variations in the food effect on propranolol bioavailability

Abstract

Mechanisms and variations in the food-induced increase in the bioavailability of propranolol were assessed by single-dose (80 mg) studies in healthy volunteers who took the drug on an empty stomach, immediately after a protein-rich breakfast, and together with a carbohydrate-rich, protein-poor breakfast. Concomitant intake of the protein-rich, but not the carbohydrate-rich, protein-poor breakfast, increased the bioavailability of propranolol in most, but not all, subjects. The food (protein) effect displayed much inter-individual variation, from a decrease to a 250% increase, which could be explained, at least in part, by a correlation between the oral clearance of propranolol and the food-induced increase in its bioavailability. The food effect was not associated with decreased total availability, but with delayed appearance, of the oxidative metabolites 4-OHP, NLA and PG. Hence the food (protein) effect does not seem to be caused by enzyme inhibition, but rather it is due to reduced hepatic extraction of propranolol, probably consequent to an increase hepatic entry rate. When taken together with the protein-rich breakfast, propranolol usually appeared in systemic blood at least as early as when taken on an empty stomach, implying that gastric absorption of propranolol may be possible in the presence of protein-rich food. Within the individual the food effect was reproducible, but its magnitude showed an intraindividual variation that may reflect its dependence upon the rates of gastrointestinal absorption and splanchnic-hepatic blood flow, and hence upon the rate of hepatic drug entry.

A Mechanistic Approach to Understanding the Factors Affecting Drug Absorption: A Review of Fundamentals

“…For drugs exhibiting a large first-pass effect, concomitant intake with food may increase drug availability. A classical example of this is propranolol; 79 as a result of, in part, its saturable first-pass metabolism, a foodinduced increase in hepatic drug delivery can lead to reduced presystemic metabolism. Another critical variable is the volume of fluid taken with the dose, whereby increasing the volume of fluid intake from 25 ml to 250 ml significantly increases the rate and extent of aspirin bioavailability.…”

The effect of a protein meal on zidovudine pharmacokinetics in HIV‐ infected patients.

“…Many HIV-infected patients receive protein supplements (Althoff et al, 1989). Protein-based meals can affect the pharmacokinetics of high clearance drugs (Liedholm et al, 1990;Olanoff et al, 1986). Since zidovudine is a highly cleared drug with a large first-pass effect (Blum et al, 1988), a protein-based meal may affect its bioavailability.…”

Food Increases the Bioavailability of Tolterodine but Not Effective Exposure

“…20,21 In each case, considerable increases in AUC of the parent drug are apparent when administered with food, but no change in AUC is observed for the hydroxylated metabo- lites. 19,22,23 Furthermore, there is no change in t 1/2z or t max for propranolol or propafenone with food. For both agents, the food effect increases with the extent of oral clearance.…”