RT Journal Article
SR Electronic
T1 Role of the Liver and Gut in Systemic Diphenhydramine Clearance in Adult Nonpregnant Sheep
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 297
OP 302
VO 27
IS 2
A1 Sanjeev Kumar
A1 K. Wayne Riggs
A1 Dan W. Rurak
YR 1999
UL http://dmd.aspetjournals.org/content/27/2/297.abstract
AB 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