Haloperidol Disposition Is Dependent on Debrisoquine Hydroxylation Phenotype

LLerena, Adrián; Alm, Christina; Dahl, Marja­‐Liisa; Ekqvist, Britta; Bertilsson, Leif

doi:10.1097/00007691-199204000-00003

Cited by 145 publications

(42 citation statements)

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“…These findings were consistent with findings from other studies. 12,14 However, the exposure differences attributed to CYP2D6 genotype were not sufficient to produce substantial haloperidol-induced QT c pharmacodynamic changes in PMs relative to EMs. A likely reason for this observation could be that CYP2D6 is not exclusively responsible for haloperidol disposition.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Desai

Tanus‐Santos

et al. 2003

Pharmacogenomics J

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We studied the pharmacokinetics and QT interval pharmacodynamics of a single 10 mg dose of oral haloperidol in a randomized, double-blind, placebo-controlled, crossover trial of healthy poor (PMs) and extensive (EMs) metabolizers of CYP2D6. There was a statistically significant greater mean QT c on haloperidol (421.6720.1 ms) than on placebo (408.4718.5 ms, P ¼ 0.0053) occurring 10 h post haloperidol/placebo administration. Men and women had similar ranges of QT c changes from placebo. Despite a statistically significant greater mean elimination half-life (19.173.6 vs 12.974.0 h, P ¼ 0.04) and lower mean apparent oral clearance (12.874.1 vs 27.0711.3 ml/min/kg, P ¼ 0.02) of haloperidol in CYP2D6 PMs than in EMs, this exposure change did not translate into marked QT c changes from baseline that could be considered clinically important. Although the magnitude of the mean QT c prolongation on haloperidol relative to placebo is relatively small, it may assume significance in the presence of other risk factors for QT prolongation. The Pharmacogenomics Journal (2003) 3, 105-113. doi:10.1038/sj.tpj.6500160Keywords: haloperidol; CYP2D6 genotype; QT INTRODUCTION Schizophrenia is a common psychiatric disease with a lifetime prevalence of nearly 1% of the general population 1 that is associated with an increased risk of premature death. A recent meta-analysis revealed that schizophrenic patients are 1.5 times more likely of dying from all causes compared to an age-and gendermatched cohort of the general population. 2 While it is not known how much of this excess risk can be attributed to antipsychotic-induced cardiotoxicity, it is clear that many antipsychotics are arrhythmogenic. 3 Among the antipsychotic drugs, haloperidol remains one of the most widely used worldwide. Haloperidol-induced ventricular arrhythmias of the torsades de pointes (TdP) type have been reported with a range of doses starting as low as 4 mg 4 administered over a 24 h period and as high as 825 mg 5 over a 24-h period. Cardiac side effects at high doses likely involve excessive exposure to haloperidol. However, the extent to which low doses of haloperidol contribute to QT interval prolongation in the absence of risk factors 6 such as age, concomitant medications, electrolyte imbalances, ischemic heart disease, or congenitally prolonged QT intervals is less well characterized. Prolongation of the QT interval is a biomarker for the malignant ventricular arrhythmia of TdP.In vitro cardiac electrophysiology studies that we have conducted demonstrate that supratherapeutic concentrations of haloperidol prolong the heart rate corrected QT interval (QT c ) by approximately 26% in an isolated perfused feline heart model. 7 The mechanism of haloperidol-mediated QT prolongation

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Section: Discussionmentioning

confidence: 99%

“…12,13 Multiple clinical studies have shown that CYP2D6 genotype influences haloperidol and reduced haloperidol pharmacokinetics. [14][15][16] However, it is not known to what extent CYP2D6 genotype influences haloperidol-induced QT interval pharmacodynamics.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Desai

Tanus‐Santos

et al. 2003

Pharmacogenomics J

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“…To qualify for these groups at least one of the following criteria was required: 1) The drug is an inhibitor of CYP2D6 in vitro [22]; 2) The drug has an inhibitory effect in vivo on debrisoquine/sparteine hydroxylation [23][24][25][26]; 3) The drug is dependent on CYP2D6 for its own metabolism [11,[27][28][29][30][31][32]. Table 2 summarizes the data on the interacting drugs.…”

Section: Study Populationmentioning

confidence: 99%

Population pharmacokinetics of nortriptyline during monotherapy and during concomitant treatment with drugs that inhibit CYP2D6‐an evaluation with the nonparametric maximum likelihood method.

Jerling

Merlé

Mentré

et al. 1994

Brit J Clinical Pharma

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“…In vitro (Inaba et al, 1985;Tyndale et al, 1991) and in vivo (Gram et al, 1989;Llerena et al, 1992a, b) studies have suggested the involvement of CYP2D6 in the metabolism of HAL, and the disposition of HAL is related to the polymorphic debrisoquine oxidation phenotype, which represents the activity of CYP2D6. Llerena et al (1992a, b) investigated the metabolism of HAL and RHAL after single doses of HAL in extensive metabolizers (EMs) and poor metabolizers (PMs) of debrisoquine, finding the clearance of HAL to be significantly lower in PMs than in EMs.…”

Section: Introductionmentioning

confidence: 99%

“…Llerena et al (1992a, b) investigated the metabolism of HAL and RHAL after single doses of HAL in extensive metabolizers (EMs) and poor metabolizers (PMs) of debrisoquine, finding the clearance of HAL to be significantly lower in PMs than in EMs. Also, plasma levels of RHAL were significantly higher in PMs than in EMs.…”

Section: Introductionmentioning

confidence: 99%

Effect of CYP2D6 Genotypes on the Metabolism of Haloperidol in a Japanese Psychiatric Population

Someya

Saito

Suzuki

et al. 2003

Neuropsychopharmacol

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We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/ CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14 7 0.69 ng/ml/mg) and RHAL (1.10 7 1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL ¼ 0.68 7 0.31 ng/ml/mg, RHAL ¼ 0.28 7 0.37 ng/ml/mg), those with one CYP2D6*10 (HAL ¼ 0.70 7 0.23 ng/ ml/mg, RHAL ¼ 0.31 7 0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL ¼ 0.69 7 0.14 ng/ml/mg, RHAL ¼ 0.40 7 0.09 ng/ ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (o10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43 7 0.23 ng/ml/mg, 0.34 7 0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18 7 0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.

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Haloperidol Disposition Is Dependent on Debrisoquine Hydroxylation Phenotype

Cited by 145 publications

References 0 publications

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Population pharmacokinetics of nortriptyline during monotherapy and during concomitant treatment with drugs that inhibit CYP2D6‐an evaluation with the nonparametric maximum likelihood method.

Effect of CYP2D6 Genotypes on the Metabolism of Haloperidol in a Japanese Psychiatric Population

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