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The in vivo metabolism of the antipsychotic agent mazapertine was studied after oral administration of mazapertine succinate (40 mg/subject) to two healthy volunteers, and urine (0-24 hours) was obtained for metabolite identification using API-ionspray LC/MS and MS/MS analysis. Unchanged mazapertine (12% of the sample) plus 10 metabolites were profiled, quantified, and tentatively identified on the basis of MS data, Glusulase-hydrolysis, and by comparison to synthetic samples. The formation of mazapertine metabolites are via seven metabolic pathways: (1) phenylhydroxylation, (2) piperidyl oxidation, (3) O-dealkylation, (4) N-dephenylation, (5) oxidative N-debenzylation, (6). depiperidylation, and (7) glucuronidation. Pathways 1, 2, 5 and 7 formed 4-OH-phenyl-mazapertine (M1, 18%) and 4-OH-piperidyl (M2, 14%)-mazapertine, carboxybenzoylpiperidine (M8, 10%) and its glucuronide (M9, 14%) as four major metabolites. Six moderate and minor metabolites (M3-M7 & M10; each < or =10%) formed via a combination of pathways 1-6. Mazapertine is extensively metabolized in humans.

The pharmacokinetics and drug disposition of 14C 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoy]piperidine succinate (RWJ-37796, mazapertine, Mz) have been investigated in male and female Sprague-Dawley rats. Approximately 93% of the orally administered radioactive dose (30 mg/kg) was recovered after 7 days. Fecal elimination accounted for approximately 63% of the dose while urine accounted for 30%. The rate of elimination of 14C Mz was rapid with 81% of the total fecal and 94% of the total urinary radioactivity being excreted within 24 h. There were no significant gender differences in the overall excretion pattern. The maximal plasma concentration of Mz and total radioactivity occurred at 0.5h after dosing and plasma concentrations were consistently higher in female rats. The Mz concentration declined rapidly in plasma with a terminal half-life<2 h. The total radioactive dose in plasma displayed a considerably longer terminal half-life of 9-13 h. Mz and a total of 15 metabolites were isolated and identified in these samples. Unchanged Mz accounted for <5% of the radioactive dose in excreta samples and <8% of the sample in plasma (0-24 h). Metabolites were formed by phenyl hydroxylation, piperidyl oxidation, O-dealkylation, N-dephenylation, oxidative N-debenzylation and glucuronide conjugation.

Objectives: Second-generation antipsychotics presumably lack the typical side effects of conventional antipsychotics., Methodology: A 34 year old Caucasian woman with ICD-10 diagnosis of Recurrent depressive disorder with current moderate symptoms, and with a history of repeated self-injury was treated with lithium, clonazepam and ziprasidone., Results: On the ninth day of ziprasidone administration, galactorrhea appeared. After 36 days of ziprasidone therapy, galactorrhea persisted. The prolactin plasma level was 28 ng/ml. Thyroid tests (TSH,T3,T4) and the lithium plasma level were within the normal range during ziprasidone treatment. Two weeks after the ziprasidone withdrawal, galactorrhea disappeared and the prolactin level decreased down to 18 ng/ml., Conclusion: Psychiatrists should be aware that even second-generation antipsychotics, including ziprasidone, have a propensity to cause side-effects associated with the dopamine D2 receptor blockade, such as galactorrhea.

The pharmacokinetics, metabolism, and excretion of a new antipsychotic drug, ziprasidone, were studied in four normal male volunteers after oral administration of a single 20 mg dose of a mixture of 14C- and 3H-labeled ziprasidone. Blood, urine, and feces were collected at various intervals for determination of total radioactivity and metabolic profiles. Eleven days after the dose, 20.3 +/- 1% of the administered radioactivity was recovered in the urine and 66.3 +/- 4.8% in feces. The absorption of ziprasidone was rapid, and the C(max) for ziprasidone and metabolites occurred at 2 to 6 hr postdose. Mean peak serum concentration of unchanged drug was 45 ng/ml and a mean AUC(0-t) of 335.7 ng x hr/ml. Mean peak serum concentration of total radioactivity (average of 3H and 14C) was 91 ng-eq/ml and a mean AUC(0-t) of 724.6 ng-eq x hr/ml. On the basis of AUC(0-t) values, approximately 46% of circulating radioactivity was attributable to unchanged drug. Ziprasidone was extensively metabolized and only a small amount (<5% of the administered dose) was excreted in urine and feces as unchanged drug. Twelve metabolites in human urine and serum were identified by ion-spray LC/MS and LC/MS/MS with simultaneous monitoring of radioactivity. The major urinary metabolites were identified as oxindole-acetic acid and its glucuronide conjugate, benzisothiazole-3-yl-piperazine (BITP), BITP-sulfoxide, BITP-sulfone and its lactam, ziprasidone-sulfoxide, and sulfone similar to those identified in rats. In addition, two novel metabolic pathways (reductive cleavage and N-dearylation of the benzisothiazole ring) were identified for ziprasidone in humans. The metabolites resulted by these pathways were characterized as S-methyl-dihydroziprasidone, S-methyl-dihydro-ziprasidone sulfoxide, and 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one, respectively. Ziprasidone sulfoxide and sulfone were the major metabolites in human serum. The affinities of the sulfoxide and sulfone metabolites for 5-HT2 and D2 receptors are low with respect to ziprasidone, and are thus unlikely to contribute to its antipsychotic effects. Structures of the major metabolites were confirmed by chromatographic and spectroscopic comparisons to synthetic standards. Based on the structures of these metabolites, four routes of metabolism of ziprasidone were identified: 1) N-dealkylation of the ethyl side chain attached to the piperazinyl nitrogen, 2) oxidation at sulfur resulting in the formation of sulfoxide and sulfone, 3) reductive cleavage of the benzisothiazole moiety, and 4) hydration of the C=N bond and subsequent sulfer oxidation or N-dearylation of the benzisothiazole moiety. The identified metabolites accounted for >90% of total radioactivity recovered in urine.

Characterization of two novel benzisothiazole ring cleaved metabolites of the antipsychotic drug, ziprasidone (ZIP), in rat has been described. Metabolites designated M6 and M9 were isolated from urine and bile of the rat dosed with radiolabeled ZIP and purified by reversed phase HPLC. The chemical structures of these metabolites were assigned based on tandem mass spectrometry in combination with chemical derivatization techniques. M6 and M9 were unaffected upon treatment with N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide. Reaction of M9 with aqueous TiCl3 also did not change the HPLC retention time or the CID spectrum of metabolite M9. These data excluded the possibility that these metabolites were owing to N-oxidation and/or aromatic hydroxylation. M6 and M9 were generated only when in vitro incubations of ZIP were conducted with human liver S-9 fraction in the presence of S-adenosyl-L-methionine. Based on these data, metabolites M6 and M9 were identified as S-methyl-dihydro-ZIP and S-methyl-dihylro-ZIP-sulfoxide, respectively. The structure of M9 was unambiguously confirmed by comparing the LC/MS retention time and mass spectral data with synthetic standard. A mechanism for the formation of these metabolites from ZIP is proposed.