Abstract
PurposeThe aim of present study is to measure plasma clozapine (CLZ) and N-desmethyl clozapine (DMC) as biomarkers to correlate drug concentrations with the appearance of preclinical adverse hematic effects.MethodsA high-performance liquid chromatographic method, using a diode-array (ultraviolet) detector, was validated to obtain reliable concentrations of CLZ and DMC, its main metabolite, in plasma of 41 schizophrenic patients taking CLZ. Blood neutrophils and leucocytes counting were concurrently assessed as a proxy to subclinical adverse reactions.ResultsThe analytical method employed was linear, reproducible, and stable to measure concentrations of CLZ between 30 and 1000 ng/mL, while 12.5–560 ng/mL of the metabolite. The method allowed us to correlate CLZ plasma concentrations, the time taking CLZ and CLZ dose as determinants of neutrophils’ counting with a R2 = 0.447, using a multiple regression analysis model. Likewise, the correlation of leucocyte counting vs CLZ plasma levels and CLZ time, showed a R2 = 0.461. DMC correlated significantly with both neutrophils and leucocytes counting, but was excluded from the regression when CLZ concentration was included in the model. Finally, no other hematological adverse reactions were recorded. One patient presented a cardiovascular complication. The negative correlation between clozapine and neutrophil count observed in patients, suggest that CLZ itself, but not DMC, could be related to hematologic side-effects.ConclusionThe findings of this study, demonstrate for the first time, that plasma levels of CLZ and time taking the drug are independent determinants of blood neutrophils and leucocytes, so the monitoring of plasma CLZ may be useful in the clinic practice to determine safe dosing of the drug.
Highlights
Schizophrenia is a chronic and debilitating disease, affecting approximately 0.5% of the world population [1]
desmethyl clozapine (DMC) has been reported to be more toxic than clozapine, but the concentrations of DMC used in that study were far above those obtained by clozapine metabolism under therapeutic dosing [8]
The aim of the present study was to study the relationship between CLZ and the its main pharmacologically active metabolite, DMC plasma levels with neutrophils and leucocytes counting in schizophrenic patients taking CLZ, in order to explore the possibility that those variables are related, before a severe toxicological condition is displayed by patients
Summary
Schizophrenia is a chronic and debilitating disease, affecting approximately 0.5% of the world population [1]. It is a treatable condition, with many therapeutic alternatives, 20–30% fail to respond to treatment, and a similar fraction of treatment adherent. It has been demonstrated that clozapine is more effective than any other first- generation agents (FGA) or second-generation antipsychotics (SGA) in the treatment of resistant schizophrenia. Some studies have shown that the stable active metabolites of CLZ, such as N-desmethyl clozapine (DMC), may related to the neutrophil counting in patients. Reactive oxygen species and nitrenium ion neutralization both involve the use of reduced glutathione; noteworthy, in patients with refractory schizophrenia, the circulating glutathione levels are decreased as compared to control subjects [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
