Insights into the Food Effect?
Abstract
A mixture of amino acids inhibits propranolol metabolism in perfused rat livers. To obtain mechanistic information about the interaction, a related but less tissue-bound drug, metoprolol, was used to determine Vmax andKM for parent drug and two metabolites in the presence and absence of amino acids. Six groups of 4 livers from 24 male Sprague-Dawley rats were perfused in the single-pass mode at 3 ml/min/g liver for 130 min with oxygenated buffer containing 3.74, 4.49, 5.61, 7.48, 18.7, or 44.9 μM metoprolol. From 50 to 90 min, a balanced amino acid mixture was included in the buffer. Samples of liver effluent taken every 5 min were analyzed by HPLC for metoprolol and two metabolites, α-hydroxymetoprolol andO-demethylmetoprolol. Steady-state concentrations of drug determined before, during, and after amino acids were used to determineVmax and apparent KM values by nonlinear curve-fitting under each condition. Amino acids reversibly reduced the Vmax values of metoprolol and both metabolites by ∼50% without significantly affecting apparent KM values. As a result, large increases in availability occurred, especially at low metoprolol inlet concentrations (>90%). Amino acids also increased oxygen consumption until the effluent buffer was almost depleted. Possible mechanisms influencing Vmax include direct inhibition of metabolic enzymes by amino acids or cosubstrate (NADPH or oxygen) limitation. Amino acid-mediated pericentral oxygen depletion in the hepatic sinusoids could result in inhibition of drug-metabolizing enzymes, and is consistent with a reduction ofVmax and oxygen depletion in the effluent buffer during amino acid coinfusion. We postulate that one or more of these mechanisms could contribute to the interaction between food and high first-pass drugs observed in humans.
Footnotes
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Send reprint requests to: Dr. Hugh A. Semple, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9.
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This study was supported by the Medical Research Council of Canada, Development Grant DG-405 and by the Heart and Stroke Foundation of Saskatchewan. This work has been presented in part as an abstract [ISSX Proc. 8, 311 (1995)].
- Abbreviations used are::
- AUC
- area under the plasma concentration-time curve
- O2
- oxygen
- OH
- hydroxy
- Css
- concentration at steady-state
- tss
- time to steady-state
- Cin
- inlet concentration
- Cout
- outlet concentration
- Q
- buffer flow rate
- E
- organ extraction ratio
- CL
- organ clearance
- F
- organ availability
- ν
- velocity of metabolism
- Cout,m
- outlet concentration of metabolite
- [S]
- substrate concentration
- MW
- molecular weight
- CYP
- cytochrome P450
- Received June 18, 1996.
- Accepted December 10, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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