Pharmacokinetics of D‐propranolol following oral, intra‐arterial and intraportal administration: Contrasting effects of oral glucose pretreatment

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Abstract
Several research groups have reported that in man the oral administration of propranolol with food leads to a marked increase (about 50 per cent) in the area under the plasma concentration—time curve (AUCpo) of this well absorbed and highly metabolized drug. An acute change in hepatic metabolic enzyme activity has been postulated as one of the mechanisms which could be responsible for this observed ‘food effect’. The administration of simple carbohydrates such as glucose and fructose has been documented to influence hepatic drug metabolism. Therefore, in the present study, the effect of oral glucose (4 g kg−1 as a 50 per cent aqueous solution) on the disposition kinetics of d‐propranolol was examined in male Sprague‐Dawley rats (8 to 9 per group). Oral glucose treatment caused a statistically significant decrease (504 ± 12.3 vs 36.6 ± 15.2 min μg ml−1; p < 0.05) in the AUCpo of propranolol when this drug was given by oral intubation (10 mg kg−1). This glucose treatment also caused the apparent mean residence time of propranolol after an oral dose to increase from 0.70 ± 0.08 h to 1.79 ± 0.29 h (p < 0.05), but did not change its rate of elimination (suggesting collectively a decreased apparent intrinsic clearance and prolonged drug absorption). In a second study, the same oral glucose treatment was demonstrated to have little impact on the steady state concentrations of propranolol when this drug was infused intraarterially at a constant rate. This confirms that the systemic clearance of propranolol is influenced minimally by the glucose treatment. In a third study, propranolol was infused at a constant rate into the portal vein (pyloric vein infusion) bypassing the processes of intestinal metabolism and absorption (i.e. to remove these sources of variability associated with oral administration). Under these conditions, no significant changes in AUC or apparent mean residence time were observed for the two propranolol doses studied (10 mg kg−1 and 5 mg kg−1). We conclude that the oral glucose and oral propranolol interaction appears to be due to an alteration in the input process before drug enters the liver. Furthermore, this experimental series suggests that studies combining accurate assessments of systemic clearance (constant rate intra‐arterial infusion studies), intrnsic hepatc clearance (pyloric en infusion studies), ad oral administration supplemented wth necessary protein binding studies may be used together to charenterize te mechanism responsible for drug‐nutrient and drug‐drug interactions.