RADIOIMMUNOASSAY FOR 7-HYDROXY METABOLITE OF FLUPHENAZINE AND ITS APPLICATION TO PLASMA-LEVEL MONITORING IN SCHIZOPHRENIC-PATIENTS TREATED LONG-TERM WITH ORAL AND DEPOT FLUPHENAZINE

Immunization of New Zealand white rabbits with a bovine serum albumin conjugate of 7-hydroxy-N-carboxyethyl-N-deshydroxyeth azine produced h ighly specific antisera for 7-hydroxyfluphenazine (7-OHFLU). A radioim munoassay (RIA) was developed using antisera from one of the rabbits t hat enabled for the first time the determination of plasma levels of 7 -OHFLU, an active metabolite of fluphenazine (FLU), in patients treate d with oral FLU dihydrochloride or i.m. FLU decanoate. The assay metho d provided sufficient sensitivity to determine accurately 20 pg of 7-O HFLU in 200 mu l (0.1 ng/ml) of plasma with a coefficient of variation of <10%. The antiserum used in the RIA for 7-OHFLU demonstrated negli gible cross-reactivity with FLU and its metabolites such as FLU sulfox ide, N-deshydroxyethylFLU, FLU N-4'-oxide, N-deshydroxyethyl-7-OHFLU, and 7-O-glucuronide of FLU and also with other antipsychotic agents an d commonly coadministered drugs. The 7-OHFLU was present in measurable amounts in all plasma samples obtained at 4-week intervals from patie nts receiving a daily oral dose of 5 (n = 10), 10 (n = 13), or 20 (n = 14) mg of FLU dihydrochloride. Large interindividual variations in th e plasma level of FLU and 7-OHFLU were noted and the mean plasma level s ratios of 7-OHFLU/ FLU at these doses were 2.07 +/- 1.08, 2.07 +/- 1 .13, and 2.02 +/- 0.82, respectively. In the case of plasma samples fr om patients treated with a biweekly i.m. dose of 5 mg of FLU decanoate , 7-OHFLU could be determined in 64% of the plasma samples where the m ean plasma level ratio of 7-OHFLU/FLU was 0.60 +/- 0.45. These data in dicate that 7-OHFLU is a major metabolite when FLU is administered eit her orally or intramuscularly to schizophrenic patients.