UPLC/ESI‐MS/MS‐based determination of metabolism of several new illicit drugs, ADB‐FUBINACA, AB‐FUBINACA, AB‐PINACA, QUPIC, 5F‐QUPIC and <i>α</i>‐PVT, by human liver microsome

Takayama, Tadateru; Suzuki, Mayu; Todoroki, Kenichiro; Inoue, Kōichi; Min, Jun Zhe; Kikura‐Hanajiri, Ruri; Goda, Yukihiro; Toyo’oka, Toshimasa

doi:10.1002/bmc.3155

Cited by 65 publications

(58 citation statements)

References 30 publications

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“…These effects could be reversed by the use of a CB1 antagonist, confirming case reports in humans. 28 Takayama et al 29 performed an important experiment about ADB-FUBINACA, AB-FUBINACA, AB-PINACA, QUPIC, and 5F-QUPIC, by using liver microsomes in 2014. Dimethyl sulfoxide (DMSO) was dissolved with 2μL of 5mM parent substrate (ADB-FUBINACA, AB-PINACA, AB-FUBINACA, QUPIC 5 F-QUPIC), and combined with freshly prepared solutions of the NADPH regeneration system solutions.…”

Section: Pharmacology and Toxicologymentioning

confidence: 99%

“…The identification of the metabolites derived from ADBFUBINACA, AB-FUBINACA, AB-PINACA, QUPIC, and 5 F-QUPIC, were determined by comparison of the MS data, selected ion chromatograms (SICs), and MS/MS product ion spectra before and after the metabolism reaction by the human liver microsomes. 29 Debruyne & Le Boisselier 30 reviewed information from clinical professionals and found that as a general rule, the synthetic cannabinoids that acted as agonists show little selectivity between the two receptors, while those that act as antagonists are highly selective in vitro. In mice, the group also described agonistic binding to CB1 receptors resulting in euphoria, anxiety, or alteration of memory.…”

Section: Pharmacology and Toxicologymentioning

confidence: 99%

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How Present Synthetic Cannabinoids Can Help Predict Symptoms in the Future

Mozayani¹

2016

MOJT

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Abbreviations: SCs, synthetic cannabinoids; Δ-9-THC, delta-9-tetrahydracannabinol; UHPLC, ultra high performance liquid chromatography; DAD, photodiode array; MS, mass spectrometry; GC, gas chromatography; DART, direct analysis in real time; TOF, time of flight spectrometry; NMR, nuclear magnetic resonance; ATR, attenuated total resonance; FTIR, fourier transform infrared spectrometry; TIC, total ion chromatogram; LC-MS/MS, liquid chromatography tandem mass spectrometry; CNS, central nervous system; LOD, limit of detection; LOQ, limit of quantitation; ULOL, upper limit of linearity; DUID, driving under the influence of drug; HLM, human liver microsomes; HPM, human pulmonary microsomes; CES 1, carboxylesterase 1 IntroductionSynthetic cannabinoids (SCs) are synthetic compounds sprayed on herbal products and have spread worldwide since 2004. Many of these compounds, more specifically l-valinamides and l-tert-leucinamides, are often characterized as part of the third, fourth and fifth generation of synthetic cannabinoids. There are many street names for herbal like compounds which are sprayed with these compounds, referred to as "Spice" such as Spice Diamond, Spice Gold, Spice Arctic Energy, Magic, Voodoo and Yucatan Fire. Such drugs are easily obtainable via the Internet, in smoke shops, and street markets. To evade law enforcement, these herbal incense products are often labeled "not for human consumption". Despite this, many countries have entered many synthetic cannabinoids to schedule 1. 1,2Initial reports of synthetic cannabinoids (SCs) in Unites States were in November 2008. In December 2008, German forensic laboratories initially identified JWH-018 and cannabicyclohexanol (CP-47,497 C8 homologue). The synthetic cannabinoids are frequently applied on plant material and inhaled. In January 2010, the popularity of these cannabinoids and their associated products appeared to have increased in the United States.3 Numerous SCs have been identified as adulterants, which have been seized by law enforcement. JWH-018, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homologues were the first SCs identified as being abused. New generations of synthetic cannabinoids quickly emerged to evade law enforcement. After various laws were passed in the United States, different generations of SCs emerged varying only by slight modifications in structure. Some recent SCs include AB-CHMINACA and AB-PINACA. These substances are commonly marketed under the guise of being a ''legal high'' with a disclaimer of ''not for human consumption''. Law enforcement, public health officials, and clinicians are encountering cases in which there has been abuse of these substances, 4 requiring up to date information of the drug legislation, chemistry of the compounds and their detection, as well as the toxicology to be able to help identify these compounds when they present clinically.After the passage of the Synthetic Drug Abuse Prevent Act of 2012 in the United States, a third and fourth generation of SCs including UR-144, XLR11, and AKB-48 emerged...

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Section: Pharmacology and Toxicologymentioning

confidence: 99%

Section: Pharmacology and Toxicologymentioning

confidence: 99%

How Present Synthetic Cannabinoids Can Help Predict Symptoms in the Future

Mozayani¹

2016

MOJT

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“…While providing the most reliable data [15], self-administration of drugs is difficult due to possible side effects and ethical concerns and therefore other approaches are commonly taken such as in vitro human hepatocytes [7][8][9][16][17][18][19][20] and human liver microsomes (HLM) [6,14,[21][22][23][24][25][26], and in vivo animals [5,[25][26][27]. The combination of controlled experiments such as human hepatocytes and authentic human urine analysis particularly appears to be valuable [28,29].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Profile of Synthetic Cannabinoids 5F-PB-22, PB-22, XLR-11 and UR-144 by Cunninghamella elegans

Watanabe

Kuzhiumparambil

Nguyen

et al. 2017

AAPS J

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The knowledge of metabolic profile of synthetic cannabinoids is important for the detection of the drugs in urinalysis due to the typical absence or low abundance of parent cannabinoids in human urine. The fungus Cunninghamella elegans has been reported to be a useful tool for metabolism study and thus applicability to synthetic cannabinoids metabolism was examined. In this study, 8-quinolinyl 1-(5-fluoropentyl)-1H-indole-3-carboxylate (5F-PB-22), 8-quinolinyl 1-pentyl-1H-indole-3-carboxylate (PB-22), [1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone (XLR-11) and (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (UR-144) were incubated with Cunninghamella elegans and the metabolites were identified using liquid chromatographyquadrupole time-of-flight mass spectrometry. The obtained metabolites were compared with reported human metabolites to assess the suitability of the fungus to extrapolate human metabolism. 5F-PB-22 underwent, dihydroxylation, dihydrodiol formation, oxidative defluorination, oxidative defluorination to carboxylic acid, ester hydrolysis and glucosidation, alone and/or in combination. The metabolites of PB-22 were generated by hydroxylation, dihydroxylation, trihydroxylation, dihydrodiol formation, ketone formation, carboxylation, ester hydrolysis and glucosidation, alone and/or in combination. XLR-11 was transformed through hydroxylation, dihydroxylation, aldehyde formation, carboxylation, oxidative defluorination, oxidative defluorination to carboxylic acid and glucosidation, alone and/or in combination. UR-144 was metabolised by hydroxylation, dihydroxylation, trihydroxylation, aldehyde formation, ketone formation, carboxylation, N-dealkylation and combinations. These findings were consistent with previously reported human metabolism except for the small extent of ester hydrolysis observed and absence of glucuronidation. Despite the limitations, Cunninghamella elegans demonstrated the capacity to produce a wide variety of metabolites including some major human metabolites of XLR-11 and UR-144 at high abundance, showing the potential for metabolism of newly emerging synthetic cannabinoids.

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“…However, they are in trace amount without showing analytical importance. Moreover, Takayama et al [2014] incubated several substrates including AB‐FUBINACA with human liver microsomes, which yielded one mono‐hydroxylated metabolite. Thomsen et al [2015] did the similar experiment incubated several substrates including AB‐FUBINACA with human liver microsomes.…”

Section: Discussionmentioning

confidence: 99%

“…It is possible to set multiple acquisition cycles to screen by liquid chromatography tandem mass spectrometry (LC‐MS/MS) [Freijo et al, 2014], but we employed this technique to perform structural studies of putative hydroxylation sites. A recent study reported the findings of metabolites by incubating AB‐FUBINACA in human liver microsomes [Takayama et al, 2014]; our study is the first to determine the metabolites of AB‐FUBINACA excreted in rat urine and to investigate its effect on gene expressions on heart and liver.…”

mentioning

confidence: 93%

Detection and Characterization of the Effect of AB‐FUBINACA and Its Metabolites in a Rat Model

Chen

Dip

Ahmed

et al. 2015

J of Cellular Biochemistry

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Synthetic cannabinoids were originally developed by academic and pharmaceutical laboratories with the hope of providing therapeutic relief from the pain of inflammatory and degenerative diseases. However, recreational drug enthusiasts have flushed the market with new strains of these potent drugs that evade detection yet endanger public health and safety. Although many of these drug derivatives were published in the medical literature, others were merely patented without further characterization. AB‐FUBINACA is an example of one of the new indazole‐carboxamide synthetic cannabinoids introduced in the past year. Even though AB‐FUBINACA has become increasingly prominent in forensic drug and toxicology specimens analyses, little is known about the pharmacology of this substance. To study its metabolic fate, we utilized Wistar rats to study the oxidative products of AB‐FUBINACA in urine and its effect on gene expressions in liver and heart. Rats were injected with 5 mg/kg of AB‐FUBINACA each day for 5 days. Urine samples were collected every day at the same time. On day 5 after treatment, we collected the organs such as liver and heart. The urine samples were analyzed by mass spectrometry, which revealed several putative metabolites and positioning of the hydroxyl addition on the molecule. We used quantitative PCR gene expression array to analyze the hepatotoxicity and cardiotoxicity on these rats and confirmed by real‐time quantitative RT‐PCR. We identified three genes significantly associated with dysfunction of oxidation and inflammation. Our study reports in vivo metabolites of AB‐FUBINACA in urine and its effect on the gene expressions in liver and heart. J. Cell. Biochem. 117: 1033–1043, 2016. © 2015 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals. Inc.

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UPLC/ESI‐MS/MS‐based determination of metabolism of several new illicit drugs, ADB‐FUBINACA, AB‐FUBINACA, AB‐PINACA, QUPIC, 5F‐QUPIC and α‐PVT, by human liver microsome

Cited by 65 publications

References 30 publications

How Present Synthetic Cannabinoids Can Help Predict Symptoms in the Future

How Present Synthetic Cannabinoids Can Help Predict Symptoms in the Future

Metabolic Profile of Synthetic Cannabinoids 5F-PB-22, PB-22, XLR-11 and UR-144 by Cunninghamella elegans

Detection and Characterization of the Effect of AB‐FUBINACA and Its Metabolites in a Rat Model

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