In vivo assessment of intestinal, hepatic, and pulmonary first pass metabolism of propofol in the rat.
OBJECTIVE
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.
Raoof
A A
AA
Pharmacokinetics Laboratory, Catholic University of Louvain (UCL), Brussels, Belgium.
Augustijns
P F
PF
Verbeeck
R K
RK
D000284:Administration, Oral; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D018938:Caco-2 Cells; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D011169:Portal Vein / Q000502:physiology; D015742:Propofol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D018686:Anesthetics, Intravenous; D015742:Propofol