%0 Journal Article %A Sanjeev Kumar %A K. Wayne Riggs %A Dan W. Rurak %T Role of the Liver and Gut in Systemic Diphenhydramine Clearance in Adult Nonpregnant Sheep %D 1999 %J Drug Metabolism and Disposition %P 297-302 %V 27 %N 2 %X 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. The American Society for Pharmacology and Experimental Therapeutics %U https://dmd.aspetjournals.org/content/dmd/27/2/297.full.pdf