Competitive displacement of clozapine from plasma proteins in normolipidemic and hyperlipidemic plasma samples: clinical implications.
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.


CONCLUSIONS
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.
Procyshyn
Ric M
RM
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada. RProcyshyn@bcmhs.bc.ca
Ho
Tiffany
T
Wasan
Kishor M
KM
D000465:Algorithms; D001667:Binding, Competitive / Q000187:drug effects; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism*; D002499:Centrifugation, Density Gradient / Q000379:methods; D008076:Cholesterol, HDL / Q000737:chemistry / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000737:chemistry / Q000378:metabolism; D019411:Clinical Laboratory Techniques / Q000379:methods; D003024:Clozapine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism; D013678:Technology, Pharmaceutical / Q000379:methods; D014316:Tritium; D014859:Warfarin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D001798:Blood Proteins; D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; D008077:Lipoproteins, LDL; D014316:Tritium; D014859:Warfarin; D003024:Clozapine