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MDL 72,222 a potent serotonin antagonist, is being developed for use as an antiemetic drug in cancer chemotherapy. An assay method has been developed for the determination of MDL 72,222 and four metabolites: N-desmethyl-MDL 72,222 (1), 3,5-dichlorobenzoic acid (2), glycine conjugate of 2 (3), and MDL 72,222-N-oxide (4). The method involves liquid-liquid extractions, derivatization with trifluoroacetic anhydride for metabolite 1, methylation with diazomethane for metabolites 2 and 3, reduction with titanous chloride for 4, and detection of each analyte by GC-MS. In this method d3-MDL 72,222, a 3-methyl-5-chlorobenzoate analogue of 1 (5), and 3,4-dichlorobenzoate analogues of 2-4 (6-8) are used as internal standards for the determination of MDL 72,222 and metabolites 1, 2, 3, and 4, respectively. The method is suitable for quantification of MDL 72,222 and the metabolites 1-4 over a concentration range of 1-150, 0.5-75, 1-150, 0.5-75, and 1-150 ng/ml, respectively. The interday precision and accuracy values are within 10% RSD and 92-110%, respectively. The interday precision and accuracy values are within 14% RSD and 87.6-116%, respectively. The method is specific and sensitive for the analysis of MDL 72,222 and four metabolites in monkey plasma. The assay method has been utilized in analyzing pharmacokinetic study samples. |
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