Sulphonylurea physicochemical-pharmacokinetic relationships in the pancreas and liver
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This study examined the physicochemical-pharmacokinetic relationships for the sulphonylureas in the perfused rat pancreas and liver. Multiple indicator dilution studies were conducted with bolus injections of tolbutamide, chlorpropamide, gliclazide, glipizide, glibenclamide and glimepiride, and a reference marker albumin, in the perfused pancreas and liver. Individual solute pharmacokinetics were analysed using nonparametric moment analysis and nonlinear regression assuming a physiologically based pharmacokinetic model. All solutes had similar shaped outflow concentration-time profiles in both the pancreas and liver, but varied in extraction. Negligible drug extraction was evident in the pancreas. Hepatic extraction ranged from 0.03 (tolbutamide) to 0.52 (glibenclamide) and could be related to solute lipophilicity and perfusate protein binding. The sulphonylurea mean transit times in both the pancreas and liver varied four- and ninefold respectively and were related to the lipophilicity and perfusate protein binding of the drug. The permeability surface area product of sulphonylureas from the perfusate into the organs were greater in the liver and were mainly determined by lipophilicity (pancreas, r2 = 0.89; liver, r2 = 0.80). The distribution of the sulphonylureas in both the perfused pancreas and perfused liver was dependent on their lipophilicity and perfusate protein binding.
Journal of Pharmaceutical Sciences
Copyright 2009 Wiley-Liss, Inc. This is the pre-peer reviewed version of the following article: Journal of Pharmaceutical Sciences Volume 98 Issue 8, Pages 2807 - 2821, which has been published in final form at http://dx.doi.org/10.1002/jps.21631