Effects of the CYP2D6*10 alleles and co‐medication with CYP2D6‐dependent drugs on risperidone metabolism in patients with schizophrenia

Yagihashi, Tatsuhiko; Mizuno, Masafumi; Chino, Bun; Sato, Yuji; Sakuma, Kei; Takebayashi, Toru; Takahashi, Tsuyoshi; Kosaki, Kenjiro

doi:10.1002/hup.1025

Cited by 20 publications

(20 citation statements)

References 37 publications

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“…The CYP2D6*10 polymorphism, which is a prevalent mutant allele among East Asians, and the presence of co-medication exert significant influences on the pharmacokinetics of risperidone [150]. …”

Section: Pharmacogenomicsmentioning

confidence: 99%

Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

et al. 2010

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About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. 10-20% of Western populations are defective in genes of the CYP superfamily; and the pharmacogenomic response of psychotropic drugs also depends on genetic variants associated with dementia. Prospective studies with anti-dementia drugs or with multifactorial strategies have revealed that the therapeutic response to conventional drugs in Alzheimer’s disease is genotype-specific. The disease-modifying effects (cognitive performance, biomarker modification) of therapeutic intervention are APOE-dependent, with APOE-4 carriers acting as the worst responders (APOE-3/3 > APOE-3/4 > APOE-4/4). APOE-CYP2D6 interactions also influence the therapeutic outcome in patients with dementia.

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Section: Pharmacogenomicsmentioning

confidence: 99%

Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

et al. 2010

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“…However, the effect of puerarin on CYP450s is still not very clear. In addition, the genetic polymorphisms of CYP2D6 give rise to both important interethnic variability in metabolism and the risk of treatment failure or dose-dependent drug toxicity and the CYP2D6*10 allele, which is a prevalent mutant allele among East Asians (Yagihashi et al, 2009). In this investigation we attempted to examine: The first, whether puerarin is able to affect hepatic CYP-linked drug metabolizing enzymes such as CYP2D6 and CYP1A2 in vivo.…”

Section: Introductionmentioning

confidence: 99%

The effects of Puerarin on CYP2D6 and CYP1A2 activities In vivo

et al. 2010

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Ge-gen (Radix Puerariae) is used in traditional oriental medicine for various medicinal purposes. The drug is the root of a wild leguminous creeper, Pueraria lobata (Willd) Ohwi. It possesses a high content of avonoid derivatives, the most abundant of which is puerarin. Our goal was to find the effect of puerarin on cytochrome P450 enzymes in vivo. The study was conducted in 18 male volunteers of different genotypes (CYP2D6 *1/*1, *1/*10, *10/*10). Plasma was obtained at 6 h after oral administration and urine was collected from 0 to 8 h after probe drug administration. The logarithm value of metabolic rate decrease from -0.0055 +/- 0.1887 to -0.1754 +/- 0.2411 implied puerarin inhibited activity of CYP2D6. There was no significant relationship between the inhibition with the CYP2D6 genotypes. The paraxanthin/caffeine ratio in the plasma sample at 6th hour was increased by 30 +/- 47% (p = 0.003), implied puerarin induced the activity of CYP1A2. While puerarin used together with the substrates of both enzymes, drug interaction worth the attention and at sometimes precautions are needed.

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“…Risperidone and (±)9-OH risperidone concentrations may be influenced by age 20 , renal function 16 , and factors affecting metabolism, including genetic polymorphisms, which vary among races/ethnicities, and drug interactions, namely CYP2D6- dependent and -inhibiting co-medications 21 . The potency and pharmacological profile (ratio of serotonin 2 (5-HT 2 ) receptor: dopamine 2 (D 2 ) receptor antagonism) of (±)9-OH risperidone is similar to that of risperidone 22 Risperidone and (±)9-OH-risperidone bind to 5-HT 2 and D 2 receptors with similar affinities 23 , yielding comparable therapeutic and toxic responses, hence “active moiety” refers to these compounds collectively.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetic Modeling of Risperidone and 9-Hydroxyrisperidone to Estimate CYP2D6 Subpopulations in Children and Adolescents

Sherwin

Saldaña

Bies

et al. 2012

Therapeutic Drug Monitoring

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AIM The study aims were to characterize risperidone and (±)-9-hydroxyrisperidone pharmacokinetic variability in children and adolescents and to evaluate covariate effects on pharmacokinetic parameters. METHODS Steady-state samples were drawn at pre-dose, 1, 2, 4, and 7 hours post-dose; CYP2D6 genotypes were available for 28 subjects. A non-linear mixed-effects model (NONMEM®) modeled the pharmacokinetics of risperidone and (±)-9-hydroxyrisperidone; covariates included age, weight, sex, and CYP2D6 phenotype. The model included 497 observations [risperidone (n=163), (+) and (−) 9-hydroxyrisperidone (n=334)] from 45 subjects aged 3–18.3 (mean 9.6±3.7) years, weighing 16.8–110 (43±20.2) kg. RESULTS A one-compartment mixture model described risperidone and (±)-9-hydroxyrisperidone clearances for three CYP2D6 metabolizer subpopulations: extensive (EM), intermediate (IM), and poor (PM). Weight significantly affected (±)-9-hydroxyrisperidone clearance. Clearance estimates in the mixture model were PM 9.38 L/h, IM 29.2 L/h, and EM 37.4 L/h. CONCLUSION Active moiety [risperidone plus (±)-9-hydroxyrisperidone] pharmacokinetic variability and the covariate effects were better explained with addition of metabolite pharmacokinetic parameters. This model may aid development of individualized risperidone dosing regimens in children and adolescents.

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Effects of the CYP2D6*10 alleles and co‐medication with CYP2D6‐dependent drugs on risperidone metabolism in patients with schizophrenia

Abstract: The CYP2D6*10 polymorphism and the presence of co-medication exerted significant influences on the pharmacokinetics of risperidone.

Cited by 20 publications

References 37 publications

Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

The effects of Puerarin on CYP2D6 and CYP1A2 activities In vivo

Population Pharmacokinetic Modeling of Risperidone and 9-Hydroxyrisperidone to Estimate CYP2D6 Subpopulations in Children and Adolescents

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