PLASMA-CONCENTRATIONS OF RISPERIDONE AND ITS 9-HYDROXY METABOLITE ANDTHEIR RELATIONSHIP TO DOSE IN SCHIZOPHRENIC-PATIENTS - SIMULTANEOUS DETERMINATION BY A HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION

A simple, sensitive and accurate method for the simultaneous determina tion of risperidone (RSP) and its 9-hydroxy metabolite (9-OH-RSP) in h uman plasma is described. The relationship between dose of RSP and the plasma concentration of RSP and 9-OH-RSP in a clinical situation is d iscussed. Both compounds were isolated from plasma by a simple one-ste p liquid-liquid extraction with 15% methylene chloride in pentane. Hig h-performance liquid chromatography separations were made on a cyano c olumn and the compounds were detected by electrochemical detector. The method had sufficient sensitivity to determine RSP and 9-OH-RSP accur ately at concentrations as low as 0.25 ng/ml when 1 ml of plasma is us ed for the analysis. The assay determinations were accurate, precise a nd consistent with a coefficient of variation less than 15%. Commonly co-administered drugs and other antipsychotics did not interfere with the analysis of either RSP or 9-OH-RSP There were large variations in inter- and intra-individual values of plasma concentrations of RSP and 9-OH-RSP. The 9-OH-RSP appears to be the major circulating active moi ety and its plasma concentrations were, on the average 22 fold higher than that of RSP in schizophrenic patients treated with RSP. The ratio of RSP/9-OH-RSP concentrations suggested that three of the patients m ay have deficiency in cytochrome P450 enzyme CYP 2D6. The plasma conce ntrations of RSP showed a weak relationship with the administered dail y oral dose (r = 0.4684, p = 0.01, n = 215). However, there was a good relationship between the daily dose of RSP and the plasma concentrati on of 9-OH-RSP (r = 0.6654, p = 0.01, n = 280) or the total active moi ety, sum of RSP and 9-OH-RSP concentrations (r = 0.7041, p = 0.0005, n = 280). The measurement of the total active moiety in plasma of schiz ophrenic patients may be useful for assessing the relationship between dose and plasma concentration and dose and clinical outcome of patien ts rather than measuring RSP alone.