Determination of clozapine and its N-demethylated metabolite in plasma by use of gas chromatography-mass spectrometry with single ion detection

Abstract

A gas chromatographic-mass spectrometric method with single ion detection has been developed for determination of clozapine and its N-demethylated metabolite norclozapine in plasma. Propylnorclozapine was used as internal standard and the mass spectrometer was adjusted to record the ion m/z 373 for the compounds analyzed. The precision of the method was found to be high, with a relative standard deviation of 6% or less for replicated samples. The limit of determination was 1.0 ng/ml for clozapine and 5.0 ng/ml norclozapine. A significant correlation was obtained between the daily oral dose of clozapine within the dose interval 100–800 mg/day and the plasma level of clozapine in 22 chronic schizophrenic patients. The plasma levels of clozapine and norclozapine were also significantly correlated. The quotient norclozapine/clozapine showed great interindividual variation and was not correlated to the daily dose of clozapine. The method is rapid and sensitive to allow evaluation of the pharmacokinetic properties of clozapine in the treatment of schizophrenic patients.