Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics                 and toxicity of MDMA

Yang, Jiansong; Jamei, Masoud; Heydari, Amir; Yeo, Karen Rowland; Torre, Rafael de la; Farré, Magı́; Tucker, Geoffrey T.; Rostami‐Hodjegan, Amin

doi:10.1177/0269881106065907

Cited by 81 publications

(67 citation statements)

References 25 publications

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“…MDMA seems to be responsible for the inhibition of its own detoxification process, as was previously described for CYP2D6, but our present study showed that this was also the case for CYP3A4 and CYP1A2 Yang et al, 2006). The catalytic autoinhibition by MDMA was observed in rat liver microsomes and in THLE cells expressing individual human P450 enzymes.…”

Section: Discussionsupporting

confidence: 81%

Differential Roles of Phase I and Phase II Enzymes in 3,4-Methylendioxymethamphetamine-Induced Cytotoxicity

Antolino-Lobo

Meulenbelt²,

Nijmeijer³

et al. 2010

Drug Metabolism and Disposition

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ABSTRACT:Metabolism plays an important role in the toxic effects caused by 3,4-methylenedioxymethamphetamine (MDMA). Most research has focused on the involvement of CYP2D6 enzyme in MDMA bioactivation, and less is known about the contribution of other cytochrome P450 (P450) and phase II metabolism. In this study, we researched the differential roles of phase I P450 enzymes CYP1A2, CYP3A4, and CYP2D6 and phase II enzymes glutathione S-transferase ( 3,4-Methylenedioxymethamphetamine [(MDMA) "ecstasy"] is an illicit drug of abuse that possesses stimulant and hallucinogenic properties. Chemically, it is a ring-substituted phenylamine derivate that became widely available in Europe at the beginning of the 1990s. The use of MDMA is mainly associated with nightclubs, dance music, and some subcultures, and a significantly higher level of use is being reported among young people (EMCDDA, 2008).Consumption of MDMA can lead to severe acute clinical effects such as tachycardia, hypertension, hyperthermia, intracranial hemorrhage, serotonin syndrome, and even death. Furthermore, reported chronic effects have been related to disruption of the serotonergic function (Parrott 2001; Garcia-Repetto et al., 2003;Schifano 2004;de la Torre et al., 2004;Carmo et al., 2006). Cases of hepatotoxicity due to MDMA ingestion have also been reported, yet it is probable that many more cases are subclinical and remain undetected. Subacute hepatotoxicity can ultimately lead to severe liver damage after repeated exposure, and MDMA is considered to be a cause of drug-induced liver injury.In MDMA-induced hepatotoxicity, metabolism appears to play an important role and has been the subject of several studies (Tucker et al., 1994;Malpass et al., 1999;de la Torre et al., 2000;Maurer et al., 2000;Segura et al., 2001;Jones et al., 2005;Milhazes et al., 2006;

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Section: Discussionsupporting

confidence: 81%

Differential Roles of Phase I and Phase II Enzymes in 3,4-Methylendioxymethamphetamine-Induced Cytotoxicity

Antolino-Lobo

Meulenbelt²,

Nijmeijer³

et al. 2010

Drug Metabolism and Disposition

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“…It is well established that there is inter-individual variation in the propensity for adverse effects due to ecstasy, and a number of polymorphisms affecting metabolism of ecstasy have been implicated including CYP2D6 and other CYP isoenzymes (Carmo et al, 2006;De la Torre et al, 2005;Lynch and Price, 2007;Yang et al, 2006). The genetic epidemiology of ecstasy use may be further enhanced by examining potential gene/gene or gene/environment interactions to produce anxiety and other psychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

Past 12-month and lifetime comorbidity and poly-drug use of ecstasy users among young adults in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions

Keyes

Martins

Hasin

2008

Drug and Alcohol Dependence

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Background-Ecstasy use is prevalent among young people and often co-occurs with other drug use, but little is known about the past 12-month and lifetime psychiatric comorbidity and specific additional drug abuse among young adult ecstasy users in the general population. To provide this information, we compared current ecstasy users to former users, other illicit drug users, and nonillicit drug users.Method-Data were gathered in a face-to-face survey of the United States conducted in the 2001-2002. Participants were household and group quarters residents aged 18-29 years (n = 8666). We measured current ecstasy use defined as any use in the past year; former ecstasy use as use prior to the past year only; other lifetime drug use included any drug other than ecstasy; lifetime non-illicit drug use as no illicit drug use. Associations were determined for nine other classes of illicit drugs, eight personality disorders, and seven mood and anxiety disorders.Results-Of current ecstasy users, 44% used >3 other classes of illicit drugs in the past year, compared to 1.6% of non-ecstasy drug users. Current ecstasy use was associated with current anxiety (OR = 3.7), specifically panic disorder (OR = 7.7) and specific phobia (OR = 4.1), also alcohol abuse (OR = 21.6) and dependence (OR = 4.1) and any personality disorder (OR = 5.1) compared to non-illicit drug users.Conclusions-Results indicate important differences in comorbidities of current and former ecstasy users compared to other drug users and lifetime non-illicit drug users that may affect

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“…The physiologically based model and the differential equations used by the simulator have been described previously [12]. A model incorporating competitive inhibition was used to simulate the inhibitory effects of the strong CYP3A4 inhibitor ketoconazole on the plasma concentration-time profiles of the test compound.…”

mentioning

confidence: 99%

From preclinical to human – prediction of oral absorption and drug–drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach in an industrial setting: a workflow by using case example

Sinha

Snoeys

Osselaer

et al. 2012

Biopharm & Drug Disp

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Purpose: A case example is presented in which the physiologically based modeling approach has been used to model the absorption of a lipophilic BCS Class II compound predominantly metabolized by CYP3A4, and to assess the interplay of absorption related parameters with the drug-drug interaction (DDI) potential. Methods: The PBPK model was built in the rat using Gastroplus W to study the absorption characteristics of the compound. Subsequently relevant model parameters were used to predict the non-linear human PK observed during first-in-human study after optimizing the absorption model for colonic absorption, bile micelle solubilization and unbound fraction in gut enterocytes (fu gut ) using SIMCYP W simulator. The model fitted absorption parameters were then used to assess the drug-drug interaction (DDI) potential of the test compound when administered along with multiple doses of a potent CYP 3A4 inhibitor, ketoconazole. The impact of fu gut in the extent of DDI was assessed using parameter sensitivity analysis. Results and Conclusions: After optimizing the preclinical model and taking into consideration bile micelle solubilization and colonic absorption, the non-linear pharmacokinetics of the test compound was satisfactorily predicted in man. Sensitivity analysis performed with the absorption parameter fu gut indicated that it could be an important parameter in predicting oral absorption. In addition, DDI simulations using SIMCYP W suggest that C max and AUC ratios may also be sensitive to the fu gut input in the model. Since fu gut cannot be measured experimentally, sensitivity analysis may help in assessing the importance of fu gut in human PK and DDI prediction using SIMCYP W .

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Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA

Cited by 81 publications

References 25 publications

Differential Roles of Phase I and Phase II Enzymes in 3,4-Methylendioxymethamphetamine-Induced Cytotoxicity

Differential Roles of Phase I and Phase II Enzymes in 3,4-Methylendioxymethamphetamine-Induced Cytotoxicity

Past 12-month and lifetime comorbidity and poly-drug use of ecstasy users among young adults in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions

From preclinical to human – prediction of oral absorption and drug–drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach in an industrial setting: a workflow by using case example

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