Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1

Yoo, Hee-Doo; Cho, Hea-Young; Lee, Sang-No; Yoon, Hwa Jung; Lee, Yong-Bok

doi:10.1007/s10928-012-9253-5

Cited by 24 publications

(11 citation statements)

References 41 publications

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“…[5] The metabolism of risperidone is catalyzed by cytochrome P450 2D6, 3A4, and 3A5 iso-forms and is hence influenced by genetic polymorphisms. [6,7] The same metabolic pathways were described in rats and dogs. [8] In particular, 9-hydroxyrisperidone was found to be the main plasma metabolite in all species.…”

Section: Introductionmentioning

confidence: 99%

An unusual case of risperidone instability in a fatality presenting an analytical and interpretative challenge

Taylor¹,

Elliott²

2013

Drug Testing and Analysis

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This paper describes the detection and characterization of unusual metabolite/breakdown products of the anti-psychotic drug risperidone in post-mortem blood and urine as part of a toxicological investigation into an unexpected death of a male suffering from paranoid schizophrenia prescribed risperidone and previously paroxetine. Compounds detected in the post-mortem blood and urine specimens were shown to be benzisoxazole ring scission products of risperidone and a hydroxy metabolite. These compounds are never routinely detected in blood and urine but can be present in mammalian faeces indicating that gut bacteria could be responsible for their formation. In this case, evidence for this process was demonstrated by the controlled in vitro stability study of risperidone spiked into the case blood and urine leading to the hypothesis that the post-mortem blood and urine samples analyzed could have contained bacteria with the ability to breakdown risperidone and its metabolite in this way. This finding is very unusual and has not been encountered before in any previous risperidone cases investigated by the authors, or widely reported in the post-mortem toxicological literature. However, a recently published paper has supported these findings in blood. As a result of this work, it was shown that the deceased had taken risperidone prior to death, even in the absence of any risperidone or its hydroxy metabolite(s) in the blood and urine. Given that risperidone has been reported to interact with paroxetine, the ingestion of risperidone could have been a factor that contributed to the death.

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Section: Introductionmentioning

confidence: 99%

An unusual case of risperidone instability in a fatality presenting an analytical and interpretative challenge

Taylor¹,

Elliott²

2013

Drug Testing and Analysis

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“…To understand the pharmacokinetic-pharmacogenomic implications of prescribing risperidone in medical practice, a population pharmacokinetic study reported that relative to normal/extensive CYP2D6 metabolizers, CYP2D6 (*10/*10) poor metabolizers experience a 64% slower oral clearance rate, 72% slower absorption rate in the gastrointestinal tract, and a 53% slower clearance from the central compartment of risperidone to the 9-hydroxyrisperidone metabolite compartment ( Yoo et al ., 2012 ). These are striking findings and these same CYP2D6 poor metabolizer’s experience a 3-fold increase in risperidone area-under-the-concentration-time curve (i.e.…”

Section: Discussionmentioning

confidence: 99%

An opportunity for clinical pharmacology trained physicians to improve patient drug safety: A retrospective analysis of adverse drug reactions in teenagers

Eugene

2018

F1000Res

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Background: Adverse drug reactions (ADRs) are a major cause of hospital admissions, prolonged hospital stays, morbidity, and drug-related mortality. In this study, we sought to identify the most frequently reported medications and associated side effects in adolescent-aged patients in an effort to prioritize clinical pharmacology consultation efforts for hospitals seeking to improve patient safety. Methods: Quarterly reported data were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) from the third quarter of 2014 and ending in the third quarter of 2017. We then used the GeneCards database to map the pharmacogenomic biomarkers associated with the most reported FAERS drugs. Data homogenization and statistics analysis were all conducted in R for statistical programming. Results: We identified risperidone (10.64%) as the compound with the most reported ADRs from all reported cases. Males represented 90.1% of reported risperidone cases with gynecomastia being the most reported ADR. Ibuprofen OR=188 (95% CI, 105.00 – 335.00) and quetiapine fumarate OR=116 (95% CI, 48.40 – 278.00) were associated with the highest odds of completed suicide in teenagers. Ondansetron hydrochloride OR=7.12 (95% CI, 1.59 – 31.9) resulted in the highest odds of pneumothorax. Lastly, olanzapine (8.96%) represented the compound with the most reported drug-drug interactions cases, while valproic acid OR=221 (95% CI, 93.900 – 522.00) was associated with the highest odds of drug-drug interactions. Conclusion: Despite any data limitations, physicians prescribing risperidone in males should be aware of the high rates of adverse drug events and an alternative psychotropic should be considered in male patients. Further, patients with a history of pneumothorax or genetically predisposed to pneumothorax should be considered for an alternative antiemetic to ondansetron hydrochloride, due to increased odds associated with the drug and adverse event.

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“…Risperidone displays high protein binding. At the higher doses, protein binding sites are saturated and more risperidone remains free and available for metabolism and excretion [31]. The difference between risperidone and its metabolite in dose- response pharmacokinetics can be attributed to the differences in pharmacokinetics behavior of 9-hydroxyrisperidone.…”

Section: Discussionmentioning

confidence: 99%

New Modified UPLC/Tandem Mass Spectrometry Method for Determination of Risperidone and Its Active Metabolite 9-Hydroxyrisperidone in Plasma: Application to Dose-Dependent Pharmacokinetic Study in Sprague-Dawley Rats

Ezzeldin

Tammam

Abo-Talib

2017

International Journal of Analytical Chemistry

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Sensitive and specific liquid-chromatography tandem mass spectrometry (UPLC-MS/MS) assay has been developed and validated for simultaneous quantification of risperidone (RIS) and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in rat plasma using olanzapine (OLA) as internal standard (IS). Pharmacokinetics of risperidone and its active metabolite 9-hydroxyrisperidone was compared across different doses (0.3, 1.0, and 6.0 mg/kg). Serial blood sample was collected over a time of 48 hours and analyzed for risperidone and its active metabolite 9-hydroxyrisperidone. The pharmacokinetics parameters including Cmax, tmax, and AUC were determined for risperidone and its active ingredient. The method was linear in the concentration range of 0.2–500 ng/mL for risperidone and 9-OH-risperidone, with coefficients of determination greater than 0.998 and lower limit of quantitation of 0.2 ng/mL. Blood levels of risperidone and its active metabolite were roughly dose-proportional. The method developed herein is simple and rapid and was successfully applied for dose-dependent pharmacokinetic study.

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Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1

Cited by 24 publications

References 41 publications

An unusual case of risperidone instability in a fatality presenting an analytical and interpretative challenge

An unusual case of risperidone instability in a fatality presenting an analytical and interpretative challenge

An opportunity for clinical pharmacology trained physicians to improve patient drug safety: A retrospective analysis of adverse drug reactions in teenagers

New Modified UPLC/Tandem Mass Spectrometry Method for Determination of Risperidone and Its Active Metabolite 9-Hydroxyrisperidone in Plasma: Application to Dose-Dependent Pharmacokinetic Study in Sprague-Dawley Rats

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