Effect of hypertriglyceridemia on the pharmacokinetics and blood–brain barrier penetration of clozapine and norclozapine following administration to rats

There is a long-term discussion in the literature concerning the possible link between the improved efficacy of clozapine treatment and elevated plasma triglyceride levels, but no mechanistic studies have been performed to date. The aim of this work was to investigate whether the postprandial hypertriglyceridemia affects the pharmacokinetics and brain distribution of clozapine and norclozapine. Experimental hypertriglyceridemia in rats was induced by oral administration of peanut oil and the pharmacokinetic parameters and brain penetration of clozapine and norclozapine following administration of clozapine were compared to normotriglyceridemic control animals. Moderately increased clearance of clozapine was found in hypertriglyceridemic animals compared to control group. No changes were found in penetration of compounds across the blood–brain barrier (BBB). Taken together, the results do not support the hypothesis that hypertriglyceridemia improves the effect of clozapine by altered pharmacokinetics of clozapine and norclozapine and their increased penetration across the BBB.