Toxicokinetics and analytical toxicology of the abused opioid U‐48800 — in vitro metabolism, metabolic stability, isozyme mapping, and plasma protein binding

Gampfer, Tanja M.; Richter, Lilian H.J.; Schäper, Jan; Wagmann, Lea; Meyer, Markus R.

doi:10.1002/dta.2683

Cited by 13 publications

(4 citation statements)

References 26 publications

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“…According to a previous study (Gampfer et al 2019), pHLS9 (2 mg microsomal protein/mL) was preincubated for 10 min at 37 °C with 25 μg/mL alamethicin (UGT reaction mixture solution B), 90 mM phosphate buffer (pH 7.4), 2.5 mM Mg 2+ , 2.5 mM isocitrate, 0.6 mM NADP + , 0.8 U/mL isocitrate dehydrogenase, 100 U/mL superoxide dismutase. Thereafter, 2.5 mM UDP-glucuronic acid (UGT reaction mixture solution A), 40 μM PAPS, 1.2 mM SAM, 1 mM DTT, 10 mM GSH was added.…”

Section: In Vitro Metabolic Stability Identification Of In Vitro Metmentioning

confidence: 99%

Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine

et al. 2020

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The two fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine (4F-Cy-BAP) and furanoyl-1-benzyl-4-anilinopiperidine (Fu-BAP) have recently been seized as new psychoactive substances (NPS) on the drugs of abuse market. As their toxicokinetic and toxicodynamic characteristics are completely unknown, this study focused on elucidating their in vitro metabolic stability in pooled human liver S9 fraction (pHLS9), their qualitative in vitro (pHLS9), and in vivo (zebrafish larvae) metabolism, and their in vitro isozyme mapping using recombinant expressed isoenzymes. Their maximum-tolerated concentration (MTC) in zebrafish larvae was studied from 0.01 to 100 µM. Their µ-opioid receptor (MOR) activity was analyzed in engineered human embryonic kidney (HEK) 293 T cells. In total, seven phase I and one phase II metabolites of 4F-Cy-BAP and 15 phase I and four phase II metabolites of Fu-BAP were tentatively identified by means of liquid chromatography high-resolution tandem mass spectrometry, with the majority detected in zebrafish larvae. N-Dealkylation, N-deacylation, hydroxylation, and N-oxidation were the most abundant metabolic reactions and the corresponding metabolites are expected to be promising analytical targets for toxicological analysis. Isozyme mapping revealed the main involvement of CYP3A4 in the phase I metabolism of 4F-Cy-BAP and in terms of Fu-BAP additionally CYP2D6. Therefore, drug-drug interactions by CYP3A4 inhibition may cause elevated drug levels and unwanted adverse effects. MTC experiments revealed malformations and changes in the behavior of larvae after exposure to 100 µM Fu-BAP. Both substances were only able to produce a weak activation of MOR and although toxic effects based on MOR activation seem unlikely, activity at other receptors cannot be excluded. Keywords In vitro and in vivo metabolism • Metabolic stability • LC-HRMS/MS • Zebrafish larvae • In vitro µ-opioid receptor activity Electronic supplementary material The online version of this article (

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Section: In Vitro Metabolic Stability Identification Of In Vitro Metmentioning

confidence: 99%

Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine

et al. 2020

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“…Regarding LC-HRMS/MS conditions, and according to previously published procedures, analyses were performed using a Thermo Fisher Scientific (TF, Dreieich, Germany) Dionex UltiMate 3000 RS pump consisting of a degasser, a quaternary pump, and an UltiMate Autosampler, coupled with a TF Q Exactive Plus equipped with a heated electrospray ionization (HESI)-II source (Gampfer et al . 2019).…”

Section: Methodsmentioning

confidence: 99%

Bioisosteric analogs of MDMA with improved pharmacological profile

Alberto-Silva,

Hemmer,

Bock

et al. 2024

Preprint

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Abstract3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is re-emerging in clinical settings as a candidate for the treatment of specific psychiatric disorders (e.g. post-traumatic stress disorder) in combination with psychotherapy. MDMA is a psychoactive drug, typically regarded as an empathogen or entactogen, which leads to transporter-mediated monoamine release. Despite its therapeutic potential, MDMA can induce dose-, individual-, and context-dependent untoward effects outside safe settings. In this study, we investigated whether three new methylenedioxy bioisosteres of MDMA improve its off-target profile.In vitromethods included radiotracer assays, transporter electrophysiology, bioluminescence resonance energy transfer and fluorescence-based assays, pooled human liver microsome/S9 fraction incubation with isozyme mapping, and liquid chromatography coupled to high-resolution mass spectrometry.In silicomethods included molecular docking. Compared with MDMA, all three MDMA bioisosteres (ODMA, TDMA, and SeDMA) showed similar pharmacological activity at human serotonin and dopamine transporters (hSERT and hDAT, respectively) but decreased activity at 5-HT2A/2B/2Creceptors. Regarding their hepatic metabolism, they differed from MDMA, withN-demethylation being the only metabolic route shared, and without forming phase II metabolites. Additional screening for their interaction with human organic cation transporters (hOCTs) and plasma membrane transporter (hPMAT) revealed a weaker interaction of the MDMA analogs with hOCT1, hOCT2, and hPMAT. Our findings suggest that these new MDMA analogs might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT and hDAT, but displaying a reduced activity at 5-HT2A/2B/2Creceptors and reduced hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies.

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“…Apparatus conditions were in line with a previously published study 15 . Details can be found in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

Toxic plants—Detection of colchicine in a fast systematic clinical toxicology screening using liquid chromatography–mass spectrometry

Vollmer

Wagmann

Meyer

2021

Drug Testing and Analysis

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Colchicum autumnale, which can be mistaken for Allium ursinum, contains the alkaloid colchicine potentially leading to life‐threatening up to fatal intoxications. We report two cases of acute intoxications with unexplained circumstances. Using the authors' systematic screening approaches, colchicine could be detected in blood plasma and urine samples using liquid chromatography coupled to linear ion trap mass spectrometry (LC‐ITMSn) and high‐resolution tandem mass spectrometry (LC‐HRMS/MS). Metabolites of colchicine could be identified in urine for confirmation of screening results. Gas chromatography–mass spectrometry (GC‐MS) analysis was also conducted, but colchicine could not be detected. Furthermore, colchicine concentration was estimated via LC‐HRMS/MS in plasma samples. Results of the systematic screening indicated the ingestion of colchicine from both subjects. In both cases, the parent compound was detected in blood plasma and urine using the LC‐HRMS/MS and LC‐ITMSn system. An O‐demethylation metabolite was identified in urine samples of both subjects using LC‐HRMS/MS; the N‐deacetylation product was also found in urine samples of both cases via LC‐HRMS/MS and LC‐ITMSn. The use of LC‐ITMSn resulted only in the detection of the O‐demethylation product in case 2. Plasma concentrations were estimated at 2.5 ng/ml and 4.7 ng/ml for cases 1 and 2, respectively. We demonstrated the detection of this highly toxic alkaloid in blood plasma and urine using a time‐saving and reliable clinical systematic screening. Furthermore, we identified metabolites of colchicine being rarely discussed in literature, which can be used as additional screening targets.

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Toxicokinetics and analytical toxicology of the abused opioid U‐48800 — in vitro metabolism, metabolic stability, isozyme mapping, and plasma protein binding

Cited by 13 publications

References 26 publications

Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine

Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine

Bioisosteric analogs of MDMA with improved pharmacological profile

Toxic plants—Detection of colchicine in a fast systematic clinical toxicology screening using liquid chromatography–mass spectrometry

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