Influence of posture on hepatic perfusion and the presystemic biotransformation of propranolol: Simulation of the food effect

Several research groups have reported that the oral administration of propranolol with protein-rich food leads to a marked increase (mean + 60%) in the area under the drug plasma concentration-time curve (AUC_oral) of this highly metabolized and well-absorbed drug. It has been postulated that this "food effect" is caused at least in part by a transient increase in hepatic blood flow (Q_H) with its associated decrease in first-pass metabolism (hepatic extraction is a monotonic decreasing function of Q_H). A randomized crossover study using postural manipulations to produce changes in Q_H of the magnitude observed after food consumption (20% to 50%) was performed in an attempt to isolate the contribution of transient changes in Q_H to the food effect phenomenon. A solution of 80 mg propranolol HCl was taken orally and subjects were randomly assigned to postural manipulation protocols that should change Q_H such that AUC_oral would be minimized (phase 1) or maximized (phase 2). Estimated Q_H (indocyanine green total body clearance from blood) was determined before and at three time points during each phase. It was observed that indocyanine green total body clearance during periods of standing was 15% to 40% below that observed during periods of seating (significant at p < 0.05 for many of the appropriate comparisons). However, AUC_oral for propranolol was not affected (mean ± 1 SD; AUC_phase2/AUC_phase1 = 0.98 ± 0.28) by these changes in Q_H, which are comparable to those encountered after food consumption. Thus the food effect on propranolol bioavailability is apparently not principally the result of a change in Q_H and must be due to other mechanisms such as a decrease in apparent intrinsic metabolic clearance (e.g., caused by inhibition of the mixed-function oxidase or glucuronyl-transferase systems), alterations in the plasma protein binding of drug in hepatic sinusoidal blood, or inhibition of slowly reversible intrahepatic drug binding.