1: Pharm Res 1996 Jun;13(6):891-5
In vivo assessment of intestinal, hepatic, and pulmonary first pass metabolism
of propofol in the rat.
Raoof AA, Augustijns PF, Verbeeck RK
Pharmacokinetics Laboratory, Catholic University of Louvain (UCL), Brussels,
Belgium.
PURPOSE: The relative contribution of the intestinal mucosa, liver and
lung to the in vivo disposition of propofol in the rat was investigated.
METHODS: Propofol (4.9-5.1 mg.kg-1) was administered to groups 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 the gut wall (fG),
liver (fH) and lung (fL) were calculated. In addition, transport experiments
were carried out using Caco-2 cell monolayers to rule out the possibility
that intestinal permeability is limiting the oral absorption of propofol.
RESULTS: Values for fG, fH and fL were the following: 0.21 +/- 0.07, 0.61
+/- 0.13, and 0.82 +/- 0.09, respectively. The apparent permeability coefficient
of propofol 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 for
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 demonstrated during the flux
experiments across the Caco-2 cell monolayers.
CONCLUSIONS: The intestinal mucosa is the main site of first pass metabolism
following oral administration of propofol in the rat. Intestinal metabolism
could therefore also contribute to the systemic clearance of propofol.
PMID: 8792428, UI: 96384540