Abstract
We investigated the contribution of the liver and gut to systemic diphenhydramine (DPHM) clearance in adult nonpregnant sheep in two separate studies. In the first study, a simultaneous 50-mg bolus each of DPHM and its deuterium-labeled analog ([2H10]DPHM) was administered to five sheep via the femoral (i.v.) and the portal venous (p.v.) routes in a randomized manner. Arterial plasma concentrations of DPHM, [2H10]DPHM, and their deaminated metabolites, DPMA (diphenylmethoxyacetic acid) and [2H10]DPMA, were measured using gas chromatography–mass spectrometry. The hepatic first-pass extraction of DPHM after p.v. administration was 94.2 ± 3.7%. However, the area under the plasma concentration versus time profile of the metabolite after i.v. dosing was only 32.5 ± 14.0% relative to that after p.v. administration. Thus, only ∼32.5% of the i.v. dose is metabolized in the liver and a significant extrahepatic systemic clearance component is evident. Using the calculated total hepatic blood flow values, it was found that 98.6 ± 9.2% of the i.v. dose eventually was delivered to the “hepatoportal” system. Because the drug delivered to the hepatoportal system is almost completely eliminated in a single pass (hepatic extraction ∼94%), this indicates a lack of any significant pulmonary drug uptake. Also, because only ∼32.5% of the i.v. dose is metabolized in liver, the gut is most likely responsible for the clearance of the remainder. This gut contribution to systemic DPHM clearance was confirmed in a separate direct study in four sheep where the steady-state DPHM gut extraction ratio was 49.0 ± 3.0%. Thus, gut accounts for a significant proportion (≥50%) of DPHM systemic clearance in sheep in spite of a very high hepatic drug extraction efficiency.
Footnotes
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Send reprint requests to: Dr. K. Wayne Riggs, Associate Professor, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3. E-mail: riggskw{at}unixg.ubc.ca
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↵1 Present address: Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065-0900.
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These studies were supported by funding from the Medical Research Council of Canada. S.K. was supported by a University of British Columbia Graduate Fellowship. D.W.R. is the recipient of an investigatorship award from the British Columbia Children’s Hospital Foundation.
- Abbreviations used are::
- DPHM
- diphenhydramine
- [2H10]DPHM
- deuterium-labeled DPHM
- DPMA
- diphenylmethoxyacetic acid
- [2H10]DPMA
- deuterium-labeled DPMA
- AUC
- area under the plasma concentration versus time profile
- Cmax
- peak plasma concentration
- EH
- hepatic first-pass extraction ratio
- p.v.
- portal venous
- QH
- total hepatic blood flow
- Received July 13, 1998.
- Accepted September 28, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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