Haloperidol Metabolism and Antipsychotic Effect in Schizophrenia

Altamura, A.C.; Mc, Mauri; Cavallaro, Roberto; Gorni, Alfredo

doi:10.1016/s0140-6736(87)92848-0

Cited by 21 publications

(1 citation statement)

References 5 publications

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“…The keto group of haloperidol undergoes metabolic reduction to form reduced haloperidol, which is one of the main metabolites of haloperidol in humans [7–9]. Although the reduced haloperidol/haloperidol ratio in plasma has been reported to be related to clinical outcome [10, 11], the clinical importance of reduced haloperidol remains unclear. Reduced haloperidol is also oxidized back to haloperidol, and metabolic interconversion between haloperidol and reduced haloperidol has been observed in humans [12, 13].…”

Section: Introductionsupporting

confidence: 86%

Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients

Roh

Chung

et al. 2001

Brit J Clinical Pharma

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Aims This study was carried out to evaluate the influence of CYP2D6 genotype on the steady state plasma concentrations of haloperidol and reduced haloperidol in Korean schizophrenic patients. Methods One hundred and twenty Korean schizophrenic patients treated with various, clinically determined, doses of haloperidol (range 3–60, median 20 mg day−1) during monotherapy were recruited. CYP2D6 genotypes were determined by analysis of the CYP2D6*10 allele using allele‐specific PCR and the CYP2D6*5 allele by long‐PCR. Steady state plasma concentrations of haloperidol and reduced haloperidol were analysed by h.p.l.c. Results Twenty‐three (19.2%), 60 (50.0%), 1 (0.8%), 33 (27.5%) and 3 patients (2.5%) possessed the CYP2D6 genotypes *1/*1, *1/*10, *1/*5, *10/*10 and *10/*5, respectively. The allele frequencies of CYP2D6*1, *10 and *5 were 44.6%, 53.8% and 1.7%, respectively. Significant relationships between dose and plasma concentrations of haloperidol (linear; r2 = 0.60, P < 0.0001) and reduced haloperidol (quadratic equation; r2 = 0.67) were observed. Overall, the concentrations normalized for dose (C/D) of haloperidol were significantly different between the CYP2D6*1/*1, *1/*10 and*10/*10 genotype groups (one‐way anova; P = 0.028). No significant differences between the genotype groups were found with respect to the C/D of reduced haloperidol (P = 0.755). However, in patients with daily doses less than 20 mg, significant differences in the C/D of haloperidol (P = 0.003), but not of reduced haloperidol, were found between the three major genotype groups. In patients with doses higher than 20 mg, no differences were found between the genotype groups for either haloperidol or reduced haloperidol. 68 patients (57%) used benztropine, an antimuscarinic agent. All four patients with a *5 allele (one together with *1 and three with *10) were found to use benztropine. The patients homozygous for the *1 allele seemed to need less benztropine than the patients with one or two mutated alleles (Fisher's exact test; P = 0.036). Conclusions The dose‐corrected steady state plasma concentrations of haloperidol, but not of reduced haloperidol, were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when doses lower than 20 mg haloperidol were given. No differences were found at higher doses. These results suggest the involvement of CYP2D6 in the metabolism of haloperidol at low doses of haloperidol (< 20 mg daily), while another enzyme, probably CYP3A4, contributes at higher doses.

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Section: Introductionsupporting

confidence: 86%

Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients

Roh

Chung

et al. 2001

Brit J Clinical Pharma

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Lack of Pharmacokinetic Interaction Between Buspirone and Haloperidol in Patients with Schizophrenia

Huang

Jann

Wei

et al. 1996

The Journal of Clinical Pharma

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The pharmacokinetic interaction between buspirone and haloperidol was evaluated in schizophrenic patients in two different groups. In both groups, haloperidol doses (10-40 mg/day) remained constant for 6 weeks before the addition of buspirone 10 mg three times daily. Serial blood samples were obtained from the 11 patients in group I at baseline (before addition of buspirone) and after administration for 24 hours. The pharmacokinetic parameters of haloperidol were determined alone and with coadministration of buspirone. In group II, buspirone 10 mg three times daily was added to treatment with haloperidol in 27 patients. Blood samples were obtained before addition of buspirone and at weeks 2 and 6 of treatment with buspirone. Samples were obtained 10 to 12 hours after administration of the evening dose and before the morning dose. Haloperidol and its metabolite, reduced haloperidol (RH), were assayed by means of high-performance liquid chromatography with electrochemical detection. Significant changes in the pharmacokinetic parameters of haloperidol were not found in group I; a mean increase in the half-life (t1/2) of haloperidol from 21.5 to 28.1 hours was observed, but this finding was not statistically significant. Under steady-state conditions, plasma levels of haloperidol in the patients in group II did not change significantly from baseline to week 6. Plasma concentrations of RH remained unaltered in both groups. The results indicate that coadministration of buspirone does not markedly affect the pharmacokinetics or plasma concentrations of haloperidol.

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Enantioseparation of Reduced Haloperidol by Capillary Zone Electrophoresis with Dimethyl‐β‐Cyclodextrin

Chen

et al. 1997

J Chinese Chemical Soc

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Chiral separation of reduced haloperidol (RHP), an optically active metabolite from haloperidol, by capillary electrophoresis is described. RHP was separated on an uncoated capillary with dimethyl-f-eyclodextrin (dimethyl-~-CD) in Tris phosphate buffer using PEG 6000 as an organic additive. Several parameters affecting the separation of RHP were studied, including pH and concentration of buffer, buffer additive, and concentration of chiral selector. The migration order of the resolved RHP was assigned with reference RHP enantiomers, 141

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Haloperidol Metabolism and Antipsychotic Effect in Schizophrenia

Cited by 21 publications

References 5 publications

Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients

Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients

Lack of Pharmacokinetic Interaction Between Buspirone and Haloperidol in Patients with Schizophrenia

Enantioseparation of Reduced Haloperidol by Capillary Zone Electrophoresis with Dimethyl‐β‐Cyclodextrin

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