IN-VIVO ASSESSMENT OF INTESTINAL, HEPATIC, AND PULMONARY FIRST PASS METABOLISM OF PROPOFOL IN THE RAT

Purpose. The relative contribution of the intestinal mucosa, liver and lung to the in vivo disposition of propofol in the rat was investigat ed. Methods. Propofol (4.9 - 5.1 mg . kg(-1)) was administered to grou ps of rats (n = 4) via the intra-arterial, intravenous, hepatic portal venous and oral routes. The AUC's of propofol were estimated and the fractions of the administered dose escaping first pass metabolism by t he gut wall (f(G)), liver (f(H)) and lung (f(L)) were calculated. In a ddition, transport experiments were carried out using Caco-2 cell mono layers to rule out the possibility that intestinal permeability is lim iting the oral absorption of propofol. Results. Values for f(G), f(H) and f(L) were the following: 0.21 +/- 0.07, 0.61 +/- 0.13, and 0.82 +/ - 0.09, respectively. The apparent permeability coefficient of propofo l across Caco-2 cell monolayers was 24.2 +/- 0.3 x 10(-6) cm . sec(-1) , which is similar to the apparent permeability coefficient obtained f or propranolol (30.7 +/- 1.7 x 10(-6) cm . sec(-1)), a compound known to easily cross the intestinal epithelial membranes. The formation of propofol glucuronide, a major metabolite of propofol, could not be dem onstrated during the flux experiments across the Caco-2 cell monolayer s. Conclusions. The intestinal mucosa is the main site of first pass m etabolism following oral administration of propofol in the rat. Intest inal metabolism could therefore also contribute to the systemic cleara nce of propofol.