EFFECT OF FLOW ON FIRST-PASS METABOLISM OF DRUGS - SINGLE-PASS STUDIES ON 4-METHYLUMBELLIFERONE CONJUGATION IN THE SERIALLY PERFUSED RAT INTESTINE AND LIVER PREPARATIONS

The vascularly perfused rat intestine and liver preparations were used to examine the effect of flaw (8 and 10 ml/min) on the sequential met abolism of 4-methylumbelliferone (4MU), which forms primarily the gluc uronide conjugate (4MUG) in intestine and the sulfate conjugate (4MUS) in liver at low input concentrations of 4MU. In this system, a consta nt tracer concentration of [H-3]4MU was delivered systemically at 8 or 10 ml/min to the perfused rat small intestine preparation; the portal venous outflow perfusate at 8 and 10 ml/min was collected at steady s tate, reoxygenated acid in turn delivered to the perfused rat liver pr eparation from a second rat donor. The intestinal extraction ratio and formation 4MUG were decreased from 0.57 +/- 0.07 to 0.49 +/- 0.06 and 42 +/- 5 to 36 +/- 4% input rate, respectively, upon increasing the f low rate from 8 to 10 ml/min (P < .05). These decreases were the resul t of the reduction in transit time with increasing flows. In contrast, hepatic 4MU conjugation was increased (from 40 +/- 7% to 48 +/- 6% in put rate to intestine) upon increasing the flow rate from 8 and 10 ml/ min (P < .05), attributed primarily to increased formation of the majo r metabolite, 4 MUS, in liver (from 35 +/- 9% to 39 +/- 9% input rate to intestine). The unusual observation on increased hepatic metabolite formation with increasing flow could be rationalized. With increased flow to the serially perfused organs, there was an increased supply of substrate to the liver, the posterior organ, because of a faster inte stinal transit time. Decreased intestinal metabolism (formation of 4MU G) at increased flow was compensated by increased hepatic metabolism ( formation of 4MUS), albeit attenuated because of a faster hepatic tran sit time. The proportions of total 4MU conjugates formed (4MUG + 4MUS) across the intestine and liver remained constant at both flow rates. Hence, a rather constant overall extraction ratio (0.98 +/- 0.004 and 0.97 +/- 0.005, P > .05) existed across the two organs. The results de monstrate that the intestine, the anterior organ, plays a regulatory r ole on substrate supply to the posterior organ, the liver. With an inc rease in flow, the contribution of the intestine will decrease, wherea s the contribution of the liver will increase in the overall first-pas s metabolism.