Determination of major metabolites of MAM-2201 and JWH-122 in in vitro and in vivo studies to distinguish their intake

Jang, Moonhee; Shin, Injae; Yang, Wenjun; Chang, Hyejin; Yoo, Hye Hyun; Lee, Jaesin; Kim, Eun‐Mi

doi:10.1016/j.forsciint.2014.08.008

Cited by 37 publications

(21 citation statements)

References 21 publications

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“…These results indicate that hydroxylation to M1, oxidative defluorination to M13, and hydroxylation of M13 to M14 were the major metabolic pathways of MAM-2201 in human liver microsomes. N-(5-hydroxypentyl)-MAM-2201 (M13) was identified as a major metabolite in human liver microsomes and human urine[28], but hydroxy-MAM-2201 (M1) and hydroxy-M13 (M14) were for the first time identified as major in vitro metabolites of MAM-2201 in this study. From these results, hydroxy-MAM-2201 (M1) and hydroxy-M13 (M14) can be used with N -)-MAM-2201 (M2), and MAM-2201 pentanoic acid (M18) as abuse biomarkers of MAM-2201.…”

mentioning

confidence: 71%

“…plasma concentrations ranged from <0.1 to 49 ng/mL, indicating its extensive metabolism [19][20][21][25][26][27]. N-(5-hydroxypentyl)-MAM-2201, N-(4-hydroxyfluoropentyl)-MAM-2201, MAM-2201 pentanoic acid, and dealkyl-MAM-2201 have been identified as the metabolites of MAM-2201 in urine and hair samples from MAM-2201 abusers [27][28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

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Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes

et al. 2016

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MAM-2201 is a synthetic cannabinoid that is increasingly found in recreational drug abusers and cases of severe intoxication. Thus, characterization of the metabolic pathways of MAM-2201 is necessary to predict individual pharmacokinetics and toxicity differences, and to avoid toxic drug-drug interactions. Collectively, 19 phase 1 metabolites of MAM-2201 were identified using liquid chromatography-Orbitrap mass spectrometry following human liver microsomal incubations in the presence of NADPH: 7 hydroxy-MAM-2201 (M1-M7), 4 dihydroxy-MAM-2201 (M8-M11), dihydrodiol-MAM-2201 (M12), N-(5-hydroxypentyl)-MAM-2201 (M13), hydroxy-M13 (M14), N-dealkyl-MAM-2201 (M15), 2 hydroxy-M15 (M16, M17), MAM-2201 N-pentanoic acid (M18), and hydroxy-M18 (M19). On the basis of intrinsic clearance values in human liver microsomes, hydroxy-MAM-2201 (M1), N-(5-hydroxypentyl)-MAM-2201 (M13), and hydroxy-M13 (M14) were the major metabolites. Based on an enzyme kinetics study using human cDNA-expressed cytochrome P450 (CYP) enzymes and an immunoinhibition study using selective CYP antibodies in human liver microsomes, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes were responsible for MAM-2201 metabolism. The CYP3A4 enzyme played a prominent role in MAM-2201 metabolism, and CYP1A2, CYP2B6, CYP2C8, and CYP2C9 enzymes played major roles in the formation of some metabolites. MAM-2201 is extensively metabolized by multiple CYP enzymes, indicating that MAM-2201 and its metabolites should be used as markers of MAM-2201 abuse and toxicity. Graphical abstract In vitro metabolic pathways of MAM-2201 were characterized in human liver microsomes and recombinant CYPs using LC-HRMS analysis. Total 19 phase I metabolites were identified with predominant contribution of CYP3A4.

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confidence: 71%

Section: Introductionmentioning

confidence: 99%

Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes

et al. 2016

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“…Previous studies have shown that fluorinated synthetic cannabinoids produce the same metabolites as those of their non-fluoro analogues through hydroxylation and carboxylation [24,25]. Furthermore, our research group concluded that the concentration ratio of N-hydroxylated metabolites is a key factor for distinguishing the abuse of these drugs, especially because the availability of reference standards is limited [26,27]. Because N-hydroxylated metabolites share the same ion transitions, careful column separation is required to quantify respective metabolites.…”

Section: Introductionmentioning

confidence: 91%

“…Because N-hydroxylated metabolites share the same ion transitions, careful column separation is required to quantify respective metabolites. However, baseline chromatographic separation of N-hydroxylated metabolites has been achieved in only a few studies [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous quantification of 37 synthetic cannabinoid metabolites in human urine by liquid chromatography-tandem mass spectrometry

et al. 2015

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Despite efforts by legal authorities to control the abuse of synthetic cannabinoids, new derivatives have continually emerged on the market to circumvent regulations, and its abuse has become a threat to public health. Thus, development of analytical methods for confirming drug intake in biological fluids is essential to ensure effective drug control and to address further drug intoxication cases. Herein, a sensitive and reliable liquid chromatography-tandem mass spectrometry method was established and validated for the simultaneous determination of 37 synthetic cannabinoid metabolites, such as N-hydroxypentyl and carboxy metabolites, using 100 ll of urine. Urine specimens were treated by enzymatic hydrolysis and solid-phase extraction. Limits of detection for the evaluated drugs ranged from 0.1 to 1 ng/ml, and the linear range spanned from 0.25 or 1 to 100 ng/ml. Precision and accuracy bias were 1.4-12.1 % and -7.2-7.2 %, respectively. Matrix effects biases were in the range of 0.4 to 10.1 %, and extraction recoveries were 65-99 %. In addition, all analytes were stable under storage conditions of 4°C and -20°C for 14 days, and after three freeze-thaw cycles. The developed method was successfully applied to actual urine specimens obtained from synthetic cannabinoid users. The present method enabled simultaneous quantification of 37 synthetic cannabinoid metabolites, including their regioisomers, in urine in the field of clinical and forensic toxicology.

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“…Under the Act UR-144 and XLR-11 were added to temporary scheduled NPS for 3 years in June 2014 in South Korea. Many studies have been reported on the determination and identification of synthetic cannabinoids in urine samples [7][8][9][10], and several researches on the determination of JWH-018, JWH-073, AM-2201, JWH-122 and MAM-2201 in hair samples were reported [11,12]. However, no study on the distribution of XLR-11 and http://dx.doi.org/10.1016/j.jpba.2015.05.022 0731-7085/© 2015 Elsevier B.V. All rights reserved.…”

Section: Introductionmentioning

confidence: 99%

Determination of XLR-11 and its metabolites in hair by liquid chromatography–tandem mass spectrometry

Park

Yeon

Lee

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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Determination of major metabolites of MAM-2201 and JWH-122 in in vitro and in vivo studies to distinguish their intake

Cited by 37 publications

References 21 publications

Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes

Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes

Simultaneous quantification of 37 synthetic cannabinoid metabolites in human urine by liquid chromatography-tandem mass spectrometry

Determination of XLR-11 and its metabolites in hair by liquid chromatography–tandem mass spectrometry

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