Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Bertelsen, Kirk; Venkatakrishnan, Karthik; Moltke, Lisa L. von; Obach, R. Scott; Greenblatt, David J.

doi:10.1124/dmd.31.3.289

Cited by 245 publications

(195 citation statements)

References 31 publications

(40 reference statements)

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“…Either the formation of the carbene or catechol intermediate can lead to irreversible modification of the CYP2D6 protein, targeting either the iron center of the heme moiety (carbene) or nucleophilic groups of amino acids in, or near, the active site of CYP2D6. Thus, the generation of paroxetine reactive metabolites at the CYP2D6 active site subsequently leads to a loss of CYP2D6 catalytic activity (Bertelsen et al, 2003). As a consequence, as the paroxetine dose is increased, the concentration of CYP2D6 inhibitor would also be expected to increase (Figure 1), producing a progressive increase in the extent of inhibition and thus, decrease in enzyme activity.…”

Section: Discussionmentioning

confidence: 99%

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

Findling

Nucci

Piergies³

et al. 2005

Neuropsychopharmacol

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The current study examined the pharmacokinetics (PK), safety, and tolerability of paroxetine after repeated multiple oral dosing in children and adolescents with major depressive or obsessive-compulsive disorder. In this 6-week, open-label, repeat dose, dose-rising study, 62 patients (27 children and 35 adolescents) were treated with paroxetine 10 mg/day for the first 2 weeks of the study, 20 mg/day for the next 2 weeks, and 30 mg/day for the final 2 weeks. Pharmacokinetic sampling and safety assessments occurred at baseline and subsequently on the final treatment day of each dosing level. Between-patient variability in PK was pronounced at the 10 mg dose level, but markedly reduced at higher doses. A supra-proportional increase in plasma concentrations with increasing dose was evident in both age groups. Data for C max and AUC (0À24) indicated that, at each dose level, paroxetine steady-state systemic exposure was higher in children than in adolescents. The differences between age groups, however, diminished with each increasing dose, and were virtually abolished when differences in weight among different age groups were considered. Stepwise regression analysis indicated that both oral clearance and volume of distribution were highly dependent on paroxetine dose, cytochrome P4502D6 genotype, and weight (po0.0001), but not age or sex. Paroxetine was generally safe and well tolerated in both age groups, with the most frequently observed adverse events being largely consistent with those observed in prior paroxetine studies of adult psychiatric patients. Certain gastrointestinal and behavioral activation events (aggressive reaction and nervousness) were reported more frequently in the youngest age group.

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Section: Discussionmentioning

confidence: 99%

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

Findling

Nucci

Piergies³

et al. 2005

Neuropsychopharmacol

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“…It is noteworthy that the use of [I] in,total / K i,u predicts the fluoxetine interactions well (data not shown), albeit perhaps coincidentally. Fluoxetine is a mechanism-based inhibitor of both CYP3A4 (Mayhew et al, 2000) and CYP2C19 (McGinnity et al, 2006) but not CYP2D6 (Bertelsen et al, 2003). In addition, the major human metabolite norfluoxetine is approximately equipotent against CYP2D6 (Table 3), although the reported unbound plasma concentrations of norfluoxetine seem unlikely to account for the reported interactions (Jannuzzi et al, 2002).…”

Section: Estimation Of Fraction Metabolized By Individual Major Humanmentioning

confidence: 95%

Integrated in Vitro Analysis for the in Vivo Prediction of Cytochrome P450-Mediated Drug-Drug Interactions

McGinnity¹,

Waters²,

Tucker³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Unbound IC 50 (IC 50,u ) values of 15 drugs were determined in eight recombinantly expressed human cytochromes P450 (P450s) and human hepatocytes, and the data were used to simulate clinical area under the plasma concentration-time curve changes (␦AUC) on coadministration with prototypic CYP2D6 substrates. Significant differences in IC 50,u values between enzyme sources were observed for quinidine (0.02 M in recombinant CYP2D6 versus 0.5 M in hepatocytes) and propafenone (0.02 versus 4.1 M). The relative contribution of individual P450s toward the oxidative metabolism of clinical probes desipramine, imipramine, tolterodine, propranolol, and metoprolol was estimated via determinations of intrinsic clearance using recombinant P450s (rP450s). Simulated ␦AUC were compared with those observed in vivo via the ratios of unbound inhibitor concentration at the entrance to the liver to inhibition constants determined against rP450s ([I] in,u /K i ) and incorporating parallel substrate elimination pathways. For this dataset, there were 20% false negatives (observed ␦AUC > 2, predicted ␦AUC < 2), 77% correct predictions, and 3% false positives. Thus, the [I] in,u /K i approach appears relatively successful at estimating the degree of clinical interactions and can be incorporated into drug discovery strategies. Using a Simcyp ADME (absorption, metabolism, distribution, elimination) simulator (Simcyp Ltd., Sheffield, UK), there were 3% false negatives, 94% correct simulations, and 3% false positives. False-negative predictions were rationalized as a result of mechanism-based inhibition, production of inhibitory metabolites, and/or hepatic uptake. Integrating inhibition and reaction phenotyping data from automated rP450 screens have shown applicability to predict the occurrence and degree of in vivo drug-drug interactions, and such data may identify the clinical consequences for candidate drugs as both "perpetrators" and "victims" of P450-mediated interactions.Inhibition of cytochrome P450 (P450) metabolism is recognized as one of the more prevalent mechanisms of clinical drug-drug interactions (DDIs) and may result in serious clinical and toxicological consequences (Nelson, 2002). During the past 2 decades, both in vitro and in vivo assessments of the P450 inhibition potential and disposition of drugs have led to a relatively thorough appreciation of the underlying reasons for certain drug combinations resulting in significant clinical outcomes. Application of this knowledge has led researchers to propose strategies that assess the potential of new chemical entities to cause clinical DDIs via inhibition of P450 metabolism. As a result, in the past decade or so, in vitro screens that determine the degree of P450 inhibition have become commonplace in drug discovery screening cascades. These screens are used to evaluate and optimize potential candidate drugs and to prioritize and design suitable clinical studies.In vitro-in vivo extrapolation (IVIVE) strategies used for P450 inhibition-mediated DDIs range from simple bu...

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“…8.2 (Ki) (Ewald and Maurer, 2008) Paroxetine 0.01-0.05 (Schulz et al, 2012) 0.03-0.15 2.85 (Bertelsen et al, 2003) Clarithromycin 2.5-4 (Schulz et al, 2012) 3.3-5.4 116 (Burt et al, 2010) Saquinavir 0.1-5 (Schulz et al, 2012) 0.15-0.4 11.5 (von Moltke et al, 1998) in vitro Probe inhibitors (Dinger et al,…”

Section: Known Inhibitorsmentioning

confidence: 99%

“…A tryptamine concentration of 100 µM was chosen because at that concentrations, no or only slight inhibition could be considered as clinically irrelevant. Clinically relevant inhibitors showed IC50 values of about 100 µM (Bertelsen et al, 2003;Brosen et al, 1993;Burt et al, 2010;Ewald and Maurer, 2008;Kobayashi et al, 1998;Niwa et al, 2005;Park et al, 2003;von Moltke et al, 1998;Wang et al, 2002;Xu and Desta, 2013). Therefore, the IC50 values were only determined for TDNPS that showed inhibition of more than 50%.…”

Section: Prescreening and Determination Of Ic50 Valuesmentioning

confidence: 99%

Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class

et al. 2016

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R., Maurer, Hans H., Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class.Toxicology Letters http://dx.doi.org/10.1016/j.toxlet. 2015.11.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.  IC50 values were comparable to that of clinically relevant inhibitors. Members of the DALT family were strong inhibitors of CYP1A2 and CYP2D6 activity. 5-MeO-DALT showed in vivo inhibition against CYP1A2 activity. ABSTRACTNew psychoactive substances (NPS) are not tested for their cytochrome P450 (CYP) inhibition potential before consumption. Therefore, this potential was explored for tryptamine-derived NPS (TDNPS) including alpha-methyl tryptamines (AMTs), dimethyl tryptamines (DMTs), diallyl tryptamines (DALTs), and diisopropyl tryptamines (DiPTs) using test substrates preferred by the Food and Drug Administration in a cocktail assay. All tested TDNPS with the exception of DMT inhibited CYP2D6 activity with IC50 values below 100 µM. DALTs inhibited CYP2D6 activity similar to paroxetine and quinidine and CYP1A2 activity comparable to fluvoxamine. 5-Methoxy-N,N-diallyltryptamine reduced in vivo the caffeine metabolism in rats consistent with in vitro results. Five of the AMTs also inhibited CYP1A2 activity comparable to amiodarone. AMT and 6-F-AMT inhibited CYP2A6 activity in the range of the test inhibitor tranylcypromine. CYP2B6 activity was inhibited by 19 tryptamines, but weakly compared to efavirenz. CYP2C8 activity was inhibited by five of the tested TDNPS and three showed values comparable to trimethoprim and gemfibrozil. Six tryptamines inhibited CYP2C9 and seven CYP2C19 activities comparable to fluconazole and chloramphenicol, respectively. Nineteen compounds showed inhibition of CYP2E1 and 18 of CYP3A activity, respectively. These results showed that the CYP inhibition by TDNPS might be clinically relevant, but clinical studies are needed to explore this further.

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Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Cited by 245 publications

References 31 publications

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

Integrated in Vitro Analysis for the in Vivo Prediction of Cytochrome P450-Mediated Drug-Drug Interactions

Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class

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