Prediction of XXXX drug clearance by multiple metabolic pathways: integration of hepatic and intestinal microsomal and cytosolic data.

@entity1 @entity12325 @entity4506 @entity3045 @entity1009 @entity6900 @entity13323 @entity3092 @entity441
The current study assesses hepatic and intestinal glucuronidation, sulfation, and @entity12325 (P450) metabolism of @entity441 , @entity3092 , @entity3045 , and @entity4506 using different in vitro systems. The fraction metabolized by conjugation and P450 metabolism was estimated in liver and intestine, and the importance of multiple metabolic pathways on accuracy of clearance prediction was assessed. In vitro intrinsic sulfation clearance (CL(int, SULT)) was determined in @entity1 intestinal and hepatic cytosol and compared with hepatic and intestinal microsomal glucuronidation (CL(int, @entity6900 )) and P450 clearance (CL(int, @entity13323 )) expressed per gram of tissue. Hepatic and intestinal cytosolic scaling factors of 80.7 mg/g liver and 18 mg/g intestine were estimated from published data. Scaled CL(int, SULT) ranged between 0.7 and 11.4 ml    @entity1009 )    g(-1) liver and 0.1 and 3.3 ml    @entity1009 )    g(-1) intestine ( @entity3045 and @entity3092 were the extremes). @entity3045 was the only compound with a high extent of sulfation (51 and 28% of total CL(int) for liver and intestine, respectively) and also significant renal clearance (26-57% of observed plasma clearance). In contrast, the clearance of @entity3092 was largely accounted for by glucuronidation. Drugs metabolized by multiple pathways ( @entity441 and @entity4506 ) demonstrated improved prediction of intravenous clearance using data from all hepatic pathways (44-86% of observed clearance) compared with predictions based only on the primary pathway (22-36%). The assumption of no intestinal first pass resulted in underprediction of oral clearance for @entity441 , @entity4506 , and @entity3092 (3-22% of observed, respectively). Accounting for the intestinal contribution to oral clearance via estimated intestinal availability improved prediction accuracy for @entity441 and @entity4506 (within 2.5-fold of observed). Current findings emphasize the importance of both hepatic and intestinal conjugation for in vitro-in vivo extrapolation of metabolic clearance.
