CONCURRENT HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHIC MEASUREMENT OF LOXAPINE AND AMOXAPINE AND OF THEIR HYDROXYLATED METABOLITES IN PLASMA

The dibenzoxazepine neuroleptic loxapine, its N-demethylated metabolit e amoxapine, and their 7- and 8-hydroxymetabolites were measured simul taneously in plasma by reversed-phase high-performance chromatographic method. An original liquid-liquid extraction procedure was performed, consisting in coextraction of the substances together with a water-mi scible solvent (acetonitrile) by a non-water-miscible solvent (toluene ). The substances were separated on a 5-mu m CN 25-cm column, and elut ed with a mobile phase consisting of acetonitrile-acetic acid 0.5 N (3 0:70) and hexylamine (0.05%). They were detected by ultraviolet spectr ophotometry at 310 nm. Clozapine was used as internal standard. Linear ity was demonstrated in the range of 10 to 250 mu g/l, and detection l imits were found to be 3.5 to 6.3 mu g/l according to the substance. W ithin-day repeatability ranged from 2.7% to 6.5%, and between-day repr oducibility ranged from 0.9% to 20.2%. The extraction procedure provid ed a mean absolute recovery of 51.1% (range, 40.7% to 58.6%) with a me an coefficient of variation of 4.2%. This technique was applied to the concurrent determination of plasma concentrations of the compounds in 10 patients administered loxapine 75 to 600 mg daily. Steady state pl asma levels of loxapine were significantly correlated with oral doses (n = 10, r = 0.858, p < 0.002). In conclusion, the method proved to be a convenient and reproducible procedure allowing the simultaneous mea surement of loxapine, amoxapine, and their metabolites in patients.