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 flow (8 and 10 ml/min) on the sequential metabolism of 4-methylumbelliferone (4MU), which forms primarily the glucuronide conjugate (4MUG) in intestine and the sulfate conjugate (4MUS) in liver at low input concentrations of 4MU. In this system, a constant tracer concentration of [3H]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 state, reoxygenated and in tum delivered to the perfused rat liver preparation from a second rat donor. The intestinal extraction ratio and formation of 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 flow rate from 8 to 10 ml/min (P < .05). These decreases were the result of the reduction in transit time with increasing flows. In contrast, hepatic 4MU conjugation was increased (from 40 +/- 7% to 48 +/- 6% input rate to intestine) upon increasing the flow rate from 8 and 10 ml/min (P < .05), attributed primarily to increased formation of the major 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 intestinal transit time. Decreased intestinal metabolism (formation of 4MUG) at increased flow was compensated by increased hepatic metabolism (formation of 4MUS), albeit attenuated because of a faster hepatic transit 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 demonstrate that the intestine, the anterior organ, plays a regulatory role on substrate supply to the posterior organ, the liver. With an increase in flow, the contribution of the intestine will decrease, whereas the contribution of the liver will increase in the overall first-pass metabolism.
Chen
J
J
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Pang
K S
KS
D000818:Animals; D006923:Hymecromone / Q000031:analogs & derivatives* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
C019492:4-methylumbelliferyl sulfate; D006923:Hymecromone; C034888:4-methylumbelliferyl glucuronide