In vitro cytochrome P450 inhibition potential of methylenedioxy-derived designer drugs studied with a two-cocktail approach

Dinger, J. E.; Meyer, Markus R.; Maurer, Hans H.

doi:10.1007/s00204-014-1412-6

Cited by 31 publications

(19 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because of these data, the inhibition potentials of these drugs against CYP3A activity could be assessed as weak. showed the highest effect (Dinger et al, 2014c).…”

Section: Prescreening and Determination Of Ic50 Valuesmentioning

confidence: 95%

“…According to Dinger et al (Dinger et al, 2014c), the general inhibition potential of the TDNPS was tested using the cocktails incubated with 100 µM of each TDNPS (structures given in Fig. 1) in triplicates.…”

Section: Prescreeningmentioning

confidence: 99%

“…According to Dinger et al (Dinger et al, 2014c), the IC50 values were determined in duplicate for TDNPS, showing more than 50% inhibition of the activity of one or more isoenzymes. The TDNPS were used at ten different concentrations (0.01, 0.05, 0.1, 1, 10, 50, 100, 200, 400, 800 µM).…”

Section: Determination Of Ic50 Valuesmentioning

confidence: 99%

“…7-Me-DALT 0.14-1.7 (Elliott and Evans, 2014;Tanaka et al, 2006;Wilson et al, 2005) 0.6-6.7 0.1 (± 0.03) 5,6-MD-DALT (Dinger et al, 2014c) 0.14-1.7 (Elliott and Evans, 2014;Tanaka et al, 2006;Wilson et al, 2005) 0.5-6 0.3 (± 0.2) 26 (± 15) 58 (± 0.7) 58 (± 17) 0.4 (± 0.3) 15 (± 0.1)…”

Section: -Meo-daltmentioning

confidence: 99%

“…They can cause increased number and/or duration of hospitalization (Palleria et al, 2013). A systematic screening of methylenedioxy-derived designer drugs showed that these drugs are inhibitors of the main CYP isoenzymes, some with IC50 values in the range of clinically relevant inhibitors (Dinger et al, 2014c).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Because of these data, the inhibition potentials of these drugs against CYP3A activity could be assessed as weak. showed the highest effect (Dinger et al, 2014c).…”

Section: Prescreening and Determination Of Ic50 Valuesmentioning

confidence: 95%

Section: Prescreeningmentioning

confidence: 99%

Section: Determination Of Ic50 Valuesmentioning

confidence: 99%

Section: -Meo-daltmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

Screening of ten cytochrome P450 enzyme activities with 12 probe substrates in human liver microsomes using cocktail incubation and liquid chromatography–tandem mass spectrometry

Kim

Lee

et al. 2019

Biopharm & Drug Disp

View full text Add to dashboard Cite

Testing for potential drug interactions of new chemical entities is essential when developing a novel drug. In this study, an assay was designed to evaluate drug interactions with 10 major human cytochrome P450 (P450) enzymes incubated in liver microsomes, involving 12 probe substrates with two cocktail incubation sets used in a single liquid chromatography-tandem mass spectrometry (LC-MS/MS) run. The P450 substrate composition in each cocktail set was optimized to minimize solvent effects and mutual drug interactions among substrates as follows: cocktail A was composed of phenacetin for CYP1A2, bupropion for CYP2B6, amodiaquine for CYP2C8, diclofenac for CYP2C9, S-mephenytoin for CYP2C19, and dextromethorphan for CYP2D6; cocktail B was composed of coumarin for CYP2A6, chlorzoxazone for CYP2E1, astemizole for CYP2J2, and midazolam, nifedipine, and testosterone for CYP3A. Multiple probe substrates were used for CYP3A owing to the multiple substrate-binding sites and substrate-dependent inhibition. After incubation in human liver microsomes, each incubation mixture was pooled and all probe metabolites were simultaneously analysed in a single LC-MS/MS run. Polarity switching was used to acquire the negative-ion mode for hydroxychlorzoxazone and positive-ion mode for the remaining analytes. The method was validated by comparing the inhibition data obtained from incubation of each individual probe substrate alone and with the substrate cocktails. The half-maximal inhibitory concentration values obtained from the cocktail and individual incubations were well correlated and in agreement with previously reported values. This new method will be useful in assessing the drug interaction potential of new chemical entities during new drug development. KEYWORDS drug interaction, high-throughput screening, IC 50 , liquid chromatography-tandem mass spectrometry, new chemical entities *These authors contributed equally to this work.

show abstract

Benzo fury: A new trend in the drug misuse scene

Bravo

Carmo

Carvalho

et al. 2019

J of Applied Toxicology

View full text Add to dashboard Cite

Benzofurans, also known by users as benzo fury or benzofury, are synthetic phenethylamines and constitute the third most prominent group of new psychoactive substances (NPS). As the use of these substances has been spread as an alternative to the classic illicit psychostimulants, such as amphetamines, their legal status was reviewed, resulting in an utter prohibition of these NPS in many countries worldwide.Herein, the prevalence of abuse, chemistry, biological effects, metabolism, and the potential harms and risky behaviors associated with the abuse of benzofurans are reviewed. The congeners of this group are mainly consumed recreationally at electronic dance music parties, in polydrug abuse settings. Benzofurans preferentially act by disturbing the functioning of serotonergic circuits, which induces their entactogenic and stimulant effects and is the reason behind the considerable number of recent benzo fury-related deaths. The slight interaction of these drugs with the dopaminergic system justifies the rewarding effects of these drugs. To date, published evidence on the mechanisms of toxicity of benzo fury is very limited but a body of research is now beginning to emerge revealing an alarming public health threat regarding the abuse of these NPS.

show abstract

In vitro cytochrome P450 inhibition potential of methylenedioxy-derived designer drugs studied with a two-cocktail approach

Cited by 31 publications

References 35 publications

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

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

Screening of ten cytochrome P450 enzyme activities with 12 probe substrates in human liver microsomes using cocktail incubation and liquid chromatography–tandem mass spectrometry

Benzo fury: A new trend in the drug misuse scene

Contact Info

Product

Resources

About