Intestinal biotransformation of harmol and 1-naphthol in the rat. Further evidence of dose-dependent phase-II conjugation in situ.

This study was conducted to characterize intestinal biotransformation of harmol (HA) and 1-naphthol (NA) in the rat and to investigate whether a similar dose-dependency exists as reported previously for acetaminophen (1). HA (2-200 mumol) or NA (0.1-10 mumol) was administered intraluminally into the isolated intestinal loop preparation in situ and all mesenteric venous (portal) blood exiting from the loop was collected continuously for 60 min. At all doses of HA and NA, the glucuronic acid conjugate was readily detected in the portal blood at the first analysis time (3 min) and attained maximal blood concentrations within 6-9 min after parent compound administration. In contrast, appearance of the sulfate conjugate in the portal blood was delayed at low doses of the parent compound. The temporal lag varied inversely with the dose and was more pronounced with HA. At the highest dose of HA and NA, the sulfate conjugate was detected in the portal blood at 3 min. The glucuronic acid conjugate was the major metabolite formed at low doses of HA (less than or equal to 20 mumol) and NA (less than or equal to 1.0 mumol). However, cumulative formation of the respective glucuronic acid conjugate was similar among all doses of HA and among rats administered 1.0 and 10 mumol NA, respectively. Conversely, the extent of sulfoconjugation increased with each increment in dose and was similar to the extent of glucuronidation at the highest dose of HA and NA. These results demonstrate dose-dependent intestinal biotransformation of HA and NA in the rat in situ.(ABSTRACT TRUNCATED AT 250 WORDS)