Absorption and presystemic glucuronidation of 1-naphthol in the vasculary fluorocarbon emulsion perfused rat small intestine: the influence of the luminal flow rate and intraluminal binding.
Using an isolated vasculary perfused rat small intestine we studied the role of luminal flow rate and intraluminal binding on the absorption of 1-naphthol (1-N) and the intestinal metabolism of 1-N to 1-naphthol-beta-D-glucuronide (1-NG). Raising the luminal perfusion rate resulted in a decrease in the luminal 1-N extraction ratio and an increase in the luminal 1-N clearance Cllum. The dependency of Cllum on flow rate appeared to conform to a convective diffusion model. A differential susceptibility of 1-N absorption and the total 1-NG appearance to the luminal flow rate resulted in a flow-dependent first-pass effect of 1-N. Next, the effect of intraluminal binding on 1-N disposition was studied in experiments in which albumin was added to the luminal perfusion fluid. The unbound concentration, as the driving force for the uptake of 1-N, seems not to be rate-limiting for the appearance of 1-NG. The total appearance of 1-NG in the presence of albumin was greater than would be anticipated from the free concentration of 1-N. As a result the extent of presystemic extraction increased with increasing albumin concentration. The precise mechanisms responsible for the phenomenona are not entirely clear. Consideration of the heterogeneity in the glucuronidation capacity along the rat small intestine and along the crypt-villus axis can help to explain the obtained results.
de Vries
M H
MH
Department of Pharmacology, Faculty of Pharmacy, University of Utrecht, The Netherlands.
Hofman
G A
GA
Koster
A S
AS
Noordhoek
J
J
D000418:Albumins / Q000378:metabolism; D000818:Animals; D005466:Fluorocarbons / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D007408:Intestinal Absorption / Q000502:physiology; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D009284:Naphthols / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
D000418:Albumins; D005466:Fluorocarbons; D005965:Glucuronates; D009284:Naphthols; C029350:1-naphthol; C029091:naphthyl glucuronide