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Influence of posture on hepatic perfusion and the presystemic biotransformation of propranolol: simulation of the food effect
Author(s) -
Modi Marlene Woodruff,
Hassett James M,
Lalka David
Publication year - 1988
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1988.149
Subject(s) - propranolol , bioavailability , indocyanine green , crossover study , pharmacokinetics , oral administration , chemistry , drug metabolism , first pass effect , perfusion , time to peak , blood flow , metabolism , pharmacology , zoology , endocrinology , medicine , surgery , biochemistry , biology , placebo , alternative medicine , pathology
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 HC1 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 phase 1 = 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. Clinical Pharmacology and Therapeutics (1988) 44 , 268–274; doi: 10.1038/clpt.1988.149