The Effect of Moderate Hemodilution with Fluosol™ on Cytochrome P4502d6 Activity in the Rat

Abstract

Desmethylimipramine (desipramine, DMI) is predominantly 2-hydroxylated to 2-hydroxydesipramine, and the remainder is N-demethylated to didesmethylimipramine (DDM1) in both rats and man. DMI 2-hydroxylation is mediated by the same cytochrome P-450 isoenzyme (P4502D6) in rats and man. Fluosol hemodilution has previously been shown to influence the activity of P4502B1 and P4502B2, the cytochrome P-450 isoenzymes induced by phenobarbital in rats. In this study, DMI was used as a model substrate to investigate the influence of moderate Fluosol hemodilution on P4502D6 activity in rats. DMI total body clearance was not influenced by Fluosol hemodilution. This was an anticipated outcome since phenobarbital had a negligible effect on DMI metabolism, and Fluosol and phenobarbital affect the same isoenzymes. DMI V_dss was increased at 0.5 hour after hemodilution, but decreased from 24-72 hours. The decreased V_dss is most likely due to increased concentrations of alpha-1-acid-glycoprotein. Thus, Fluosol hemodilution is not expected to influence the hepatic P4502D6 activity in man. However, Fluosol may have marked influences on the apparent volumes of distribution of basic drugs that bind to alpha-1-acid-glycoprotein.