Extrahepatic sulfation and glucuronidation in the rat in vivo. Determination of the hepatic extraction ratio of harmol and the extrahepatic contribution to harmol conjugation.

ABSTRACT

The phenolic compound, harmol, is metabolized by sulfation and glucuronidation in the rat in vivo. In the present study, various harmol infusion rates into the jugular vein were used to delineate first-order conditions whereby total body clearance was maximal and constant; at low infusion rates the steady state harmol concentration in blood varied proportionally with the infusion rate. At infusion rates of 167 nmole/min and below, the steady state clearance of harmol was 60 ml/min or 200 ml/min/kg. Because this value for total body clearance greatly exceeded the value for hepatic blood flow rate (20 ml/min for a 300 g rat), considerable extrahepatic conjugation of harmol was suggested. At higher harmol infusion rates the total clearance decreased. Since an intraportal infusion of 167 nmole/min to the rat yielded, during steady state, the same arterial harmol blood concentration as a 52 nmole/min jugular infusion, the hepatic extraction ratio of harmol in vivo was 0.7. Extrahepatic clearance, therefore, constituted about 77% of total body clearance (after taking the difference between total body clearance and hepatic clearance). Total sulfation clearance was 52 ml/min, and greatly exceed the value for hepatic clearance (14 ml/min). Extrahepatic clearance for sulfation (at least 38 ml/min) therefore accounted for a major proportion of the sulfation activity. Blood platelets did not seem to contribute to sulfation or glucuronidation in vivo.