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 (QH) with its associated decrease in first-pass metabolism (hepatic extraction is a monotonic decreasing function of QH). A randomized crossover study using postural manipulations to produce changes in QH of the magnitude observed after food consumption (20% to 50%) was performed in an attempt to isolate the contribution of transient changes in QH 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 QH such that AUC oral would be minimized (phase 1) or maximized (phase 2). Estimated QH (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 less than 0.05 for many of the appropriate comparisons). However, AUC oral for propranolol was not affected (mean +/- 1 SD; AUC phase 2/AUC phase 1+= 0.98 +/- 0.28) by these changes in QH, which are comparable to those encountered after food consumption.(ABSTRACT TRUNCATED AT 250 WORDS)