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Vol. 27, Issue 2, 297-302, February 1999

Role of the Liver and Gut in Systemic Diphenhydramine Clearance in Adult Nonpregnant Sheep

Sanjeev Kumar,1 K. Wayne Riggs, and Dan W. Rurak

Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences (S.K. and K.W.R.) and British Columbia Research Institute of Child and Family Health, Department of Obstetrics and Gynecology, Faculty of Medicine (D.W.R.), The University of British Columbia, Vancouver, British Columbia, Canada

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.

1   Present address: Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065-0900.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics.