Abstract
This is a report of a symposium held at the March 1997 meeting of the American Society for Pharmacology and Therapeutics in San Diego. Our understanding of the events that control first-pass drug elimination in humans has increased tremendously by two sequential discoveries. First, cytochrome P-450s 3A4 and 5 are expressed at high concentrations in both hepatocytes and upper intestinal enterocytes, and therefore limit the systemic availability of many drugs. Second, P-glycoprotein is expressed at the lumenal surface of the intestinal epithelium and therefore also acts to oppose the absorption of unchanged drug. The following discussion brings together our current understandings of these interrelated phenomena to aid a more complete picture of how they may contribute both qualitatively and quantitatively to first-pass elimination.
Footnotes
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Send reprint requests to: Stephen D. Hall, Ph.D., Clinical Pharmacology, 320 OPW Wishard Hospital, 1001 West Tenth Street, Indianapolis, IN 46202. E-mail: sdhall{at}iupui.edu
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↵1 Conflict of Interest Statement: Dr. Watkins owns equity in Metabolic Solutions, Inc., (Merrimack, NH) which manufactures and sells the ERMBT kit and he is also Chairman of the Scientific Advisory Board of Avmax.
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Supported by National Institutes of Health Grants GM38149-11 (P.B.W.), GM53095-01 (K.S.L.), and MO1 RR00042 (University of Michigan General Clinical Research Center), and Grant MA-11584 from the Medical Research Council of Canada.
- Abbreviations used are::
- CYP
- cytochrome P-450
- ERMBT
- erythromycin breath test
- AUC
- area under the plasma concentration time curve
- Cmax
- maximum plasma concentration
- P-gp
- P-glycoprotein
- Vmax
- maximal rate of metabolism
- ka
- absorption rate constant
- kgm
- rate constant for gut wall metabolism
- Received August 19, 1998.
- Accepted September 1, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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Molecular and Physical Mechanisms of First-Pass Extraction
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- Role of Enterocyte CYP3A in the First-Pass Extraction of Midazolam (K.E.T., M.F.P.)
- Assessing the Role of Intestinal CYP3A4 in Limiting Oral Delivery of Drugs: New Approaches (P.B.W., D.G.B., K.S.L., R.J.F.)
- The Emerging Role of Intestinal P-Glycoprotein (MDR1) in Oral Drug Availability (K.S.L., R.R.M., D.K.T., P.B.W.)
- Overlapping Substrate Specificities of CYP3A4 and P-Glycoprotein: Implications in Drug Delivery (L.Z.B.)
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