Pharmacokinetics of D-propranolol following oral, intra-arterial and intraportal administration

Contrasting effects of oral glucose pretreatment

Hsiao-Hui Chow, D. Lalka

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 (AUC(po)) 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 carbohydrate 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 0 per group). Oral glucose treatment caused a statistically significant decrease (50.4 ± 12.3 vs 36.6 ± 15.2 min μg ml-1; p < 0.05) in the AUC (po) 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 9.70 ± 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 intra-arterially 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 suggest that studies combining accurate assessments of systemic clearance (constant rate intra-arterial infusion studies), intrinsic hepatic clearance (pyloric vein infusion studies), and oral administration supplemented with necessary protein binding studies may be used together to characterize the mechanism responsible for drug-nutrient and drug-drug interactions.

Original languageEnglish (US)
Pages (from-to)217-231
Number of pages15
JournalBiopharmaceutics and Drug Disposition
Volume14
Issue number3
StatePublished - 1993

Fingerprint

Propranolol
Pharmacokinetics
Glucose
Pharmaceutical Preparations
Area Under Curve
Oral Administration
Liver
Food
Veins
Intra Arterial Infusions
Intestinal Absorption
Therapeutics
Portal Vein
Fructose
Drug Interactions
Intubation
Protein Binding
Sprague Dawley Rats
Carbohydrates
Enzymes

Keywords

  • Food effect
  • Glucose
  • Hepatic metabolism
  • Pharmacokinetics
  • Propranolol

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

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title = "Pharmacokinetics of D-propranolol following oral, intra-arterial and intraportal administration: Contrasting effects of oral glucose pretreatment",
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 (AUC(po)) 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 carbohydrate 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 0 per group). Oral glucose treatment caused a statistically significant decrease (50.4 ± 12.3 vs 36.6 ± 15.2 min μg ml-1; p < 0.05) in the AUC (po) 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 9.70 ± 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 intra-arterially 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 suggest that studies combining accurate assessments of systemic clearance (constant rate intra-arterial infusion studies), intrinsic hepatic clearance (pyloric vein infusion studies), and oral administration supplemented with necessary protein binding studies may be used together to characterize the mechanism responsible for drug-nutrient and drug-drug interactions.",
keywords = "Food effect, Glucose, Hepatic metabolism, Pharmacokinetics, Propranolol",
author = "Hsiao-Hui Chow and D. Lalka",
year = "1993",
language = "English (US)",
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pages = "217--231",
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T1 - Pharmacokinetics of D-propranolol following oral, intra-arterial and intraportal administration

T2 - Contrasting effects of oral glucose pretreatment

AU - Chow, Hsiao-Hui

AU - Lalka, D.

PY - 1993

Y1 - 1993

N2 - 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 (AUC(po)) 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 carbohydrate 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 0 per group). Oral glucose treatment caused a statistically significant decrease (50.4 ± 12.3 vs 36.6 ± 15.2 min μg ml-1; p < 0.05) in the AUC (po) 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 9.70 ± 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 intra-arterially 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 suggest that studies combining accurate assessments of systemic clearance (constant rate intra-arterial infusion studies), intrinsic hepatic clearance (pyloric vein infusion studies), and oral administration supplemented with necessary protein binding studies may be used together to characterize the mechanism responsible for drug-nutrient and drug-drug interactions.

AB - 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 (AUC(po)) 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 carbohydrate 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 0 per group). Oral glucose treatment caused a statistically significant decrease (50.4 ± 12.3 vs 36.6 ± 15.2 min μg ml-1; p < 0.05) in the AUC (po) 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 9.70 ± 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 intra-arterially 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 suggest that studies combining accurate assessments of systemic clearance (constant rate intra-arterial infusion studies), intrinsic hepatic clearance (pyloric vein infusion studies), and oral administration supplemented with necessary protein binding studies may be used together to characterize the mechanism responsible for drug-nutrient and drug-drug interactions.

KW - Food effect

KW - Glucose

KW - Hepatic metabolism

KW - Pharmacokinetics

KW - Propranolol

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VL - 14

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JO - Biopharmaceutics and Drug Disposition

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