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Abstract
Objective, This study assesses whether competitive displacement of clozapine by warfarin affects clozapine's overall plasma distribution. Methods, Warfarin sodium was preincubated in normolipidemic and hyperlipidemic plasma samples in varying concentrations. Following the preincubation with warfarin, [3H]clozapine mixed with unlabeled clozapine was added to the plasma samples. The plasma was separated into its lipoprotein and lipoprotein-deficient fractions by density gradient ultracentrifugation, and clozapine distribution was determined. Results, When normolipidemic plasma was preincubated with various concentrations of warfarin, no significant redistribution of clozapine was noted among the various plasma lipoprotein fractions. However, in the case of the hyperlipidemic plasma, preincubating with warfarin did result in a significant redistribution of clozapine from the lipoprotein-deficient fraction to the very-low-density and low-density fractions of lipoproteins. Based on pharmacokinetic principles, the steady-state unbound concentration of clozapine in normolipidemic and hyperlipidemic plasma is not expected to change. Conclusion, Although no change in the steady-state unbound (active) concentration of clozapine would predict no change in clinical status, it is possible that this may only apply to the individuals with a normal lipid profile. We believe clozapine's association with lipoproteins (particularly triglycerides) may actually increase clozapine's effectiveness.
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Notes
a aExtraction ratio may be expressed as 100% of the drug entering the liver less the relative concentration of drug, which is removed by the liver.