Dose-dependent intestinal glucuronidation and sulfation of acetaminophen in the rat in situ.

An in situ isolated intestinal loop preparation was used to characterize intestinal phase II biotransformation of acetaminophen (AA) and to determine whether AA biotransformation is dose-dependent in the rat intestine. Under urethane-induced anesthesia, AA (6.6-66 mumol) was injected directly into the lumen of the isolated intestinal loop in situ and all mesenteric venous (portal) blood coming from the loop collected continuously for 60 min. Acetaminophen-glucuronide (AA-glucuronide) and acetaminophen-sulfate (AA-sulfate) were the only phase II metabolites of AA consistently detected. At low doses (less than or equal to 14 mumol), AA-glucuronide was the major intestinal metabolite of AA formed. Intestinal glucuronidation became saturated at higher doses of AA. The maximum concentration of AA-glucuronide attained in the portal blood was similar after administration of 14, 30 or 66 mumol of AA. In contrast, the extent of intestinal sulfation of AA increased with each increment in dose and, ultimately, exceeded intestinal glucuronidation at the highest dose studied (66 mumol). In an attempt to ameliorate saturation of intestinal glucuronidation, glucose (5 or 50 mM) was administered with 66 mumol of AA. Intestinal AA glucuronidation was unaffected by glucose coadministration. Unexpectedly, the intestinal absorption of AA was increased and sulfation of AA decreased by co-administration of glucose. These data indicate that intestinal phase II biotransformation of AA is dose-dependent, with glucuronidation predominating at low doses and sulfation increasing in importance at high doses. Furthermore, intestinal glucuronidation is capacity-limited at relatively low doses of AA. These observations demonstrate sharp contrasts between the ability of the intestine and liver to biotransform AA.