Aa. Raoof et al., IN-VIVO ASSESSMENT OF INTESTINAL, HEPATIC, AND PULMONARY FIRST PASS METABOLISM OF PROPOFOL IN THE RAT, Pharmaceutical research, 13(6), 1996, pp. 891-895
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.