Distribution of free and conjugated cannabinoids in human bile samples

Fabritius, Marie; Staub, Christian; Mangin, Patrice; Giroud, Christian

doi:10.1016/j.forsciint.2012.08.013

Cited by 43 publications

(18 citation statements)

References 21 publications

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“…[8] For hydroxy-methoxyphenyl-glucuronide (No. [28,40,41] Proposed metabolic pathways and comparison with published human data JWH-210 Figure 1d shows the metabolites found in pig urine that were also reported in human urine. The first indicated hydroxylation on the methoxyphenyl moiety and the latter fragment ion an unaltered indole-N-pentyl fragment (Figure 2b).…”

Section: Rcs-4 Metabolitesmentioning

confidence: 89%

“…In general, the findings on the fragmentation patterns of THC and its metabolites were in agreement with published data. [28,40,41] Proposed metabolic pathways and comparison with published human data JWH-210 Figure 1d shows the metabolites found in pig urine that were also reported in human urine. [10,11] In our study, the major metabolic pathways were hydroxylation at the ethyl side chain or N-pentyl side chain and combinations of them followed by glucuronidation.…”

Section: Rcs-4 Metabolitesmentioning

confidence: 89%

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Metabolic patterns of JWH‐210, RCS‐4, and THC in pig urine elucidated using LC‐HR‐MS/MS: Do they reflect patterns in humans?

Schaefer

Helfer

Kettner

et al. 2016

Drug Testing and Analysis

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The knowledge of pharmacokinetic (PK) properties of synthetic cannabinoids (SCs) is important for interpretation of analytical results found for example in intoxicated individuals. In the absence of human data from controlled studies, animal models elucidating SC PK have to be established. Pigs providing large biofluid sample volumes were tested for prediction of human PK data. In this context, the metabolic fate of two model SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4), was elucidated in addition to Δ -tetrahydrocannabinol (THC). After intravenous administration of the compounds, hourly collected pig urine was analyzed by liquid chromatography-high resolution mass spectrometry. The following pathways were observed: for JWH-210, hydroxylation at the ethyl side chain or pentyl chain and combinations of them followed by glucuronidation; for RCS-4, hydroxylation at the methoxyphenyl moiety or pentyl chain followed by glucuronidation as well as O-demethylation followed by glucuronidation or sulfation; for THC, THC glucuronidation, 11-hydroxylation, followed by carboxylation and glucuronidation. For both SCs, parent compounds could not be detected in urine in contrast to THC. These results were consistent with those obtained from human hepatocyte and/or human case studies. Urinary markers for the consumption of JWH-210 were the glucuronide of the N-hydroxypentyl metabolite (detectable for 3-4 h) and of RCS-4 the glucuronides of the N-hydroxypentyl, hydroxy-methoxyphenyl (detectable for at least 6 h), and the O-demethyl-hydroxy metabolites (detectable for 4 h). Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Rcs-4 Metabolitesmentioning

confidence: 89%

Section: Rcs-4 Metabolitesmentioning

confidence: 89%

Metabolic patterns of JWH‐210, RCS‐4, and THC in pig urine elucidated using LC‐HR‐MS/MS: Do they reflect patterns in humans?

Schaefer

Helfer

Kettner

et al. 2016

Drug Testing and Analysis

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“…Assessing DDIs based on concentrations reaching metabolic sites (i.e., liver) could generally yield a more accurate prediction. However, there are almost no data regarding cannabinoid hepatic concentrations in humans, beyond limited postmortem data, suggesting that certain cannabinoids (i.e., CBD, CBN) attain much higher concentrations in the liver and bile relative to systemic concentrations (Gronewold and Skopp, 2011;Fabritius et al, 2012). Second, in the inhibition study conducted for K i determination, all [I] values used were higher than the estimated K i values.…”

Section: Downloaded Frommentioning

confidence: 98%

In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites

2019

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The escalating use of medical cannabis and significant recreational use of cannabis in recent years has led to a higher potential for metabolic interactions between cannabis or one or more of its components and concurrently used medications. Although there have been a significant number of in vitro and in vivo assessments of the effects of cannabis on cytochrome P450 and UDP-glucuronosyltransferase enzyme systems, there is limited information regarding the effects of cannabis on the major hepatic esterase, carboxylesterase 1 (CES1). In this study, we investigated the in vitro inhibitory effects of the individual major cannabinoids and metabolites Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), 11-nor-THC-carboxylic acid, and 11-hydroxy-THC on CES1 activity. S9 fractions from human embryonic kidney 293 cells stably expressing CES1 were used in the assessment of cannabinoid inhibitory effects. THC, CBD, and CBN each exhibited substantial inhibitory potency, and were further studied to determine their mechanism of inhibition and kinetic parameters. The inhibition of CES1 by THC, CBD, and CBN was reversible and appears to proceed through a mixed competitivenoncompetitive mechanism. The inhibition constant (K i ) values for THC, CBD, and CBN inhibition were 0.541, 0.974, and 0.263 mM (0.170, 0.306, and 0.0817 mg/ml), respectively. Inhibition potency was increased when THC, CBD, and CBN were combined. Compared with the potential unbound plasma concentrations attainable clinically, the K i values suggest a potential for clinically significant inhibition of CES1 by THC and CBD. CBN, however, is expected to have a limited impact on CES1. Carefully designed clinical studies are warranted to establish the clinical significance of these in vitro findings.https://doi.org/10.1124/dmd.118.086074.ABBREVIATIONS: AUC, area under the plasma concentration-time curve; CBD, cannabidiol; CBN, cannabinol; CES1, carboxylesterase 1; DDI, drug-drug interaction; [I], inhibitor concentration; I max , maximal degree of inhibition; I max,u , maximal unbound plasma concentration of the inhibitor observed in clinical studies; K i , inhibition constant; LC-MS/MS, liquid chromatography tandem mass spectrometry; OC, oseltamivir carboxylate; 11-OH-THC, 11-hydroxy-Δ9-tetrahydrocannabinol; OST, oseltamivir phosphate; P450, cytochrome P450; R AUC , ratio of the area under plasma concentration-time curve of substrate with the presence of inhibitor over that without; R v , percentage ratio; THC, Δ9-tetrahydrocannabinol; THC-COOH, 11-nor-Δ9-tetrahydrocannabinol-carboxylic acid; UGT, UDP-glucuronosyltransferase.

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“…A number of additional hydroxylated and oxidized minor metabolites of THC [20] and CBD [31] are also formed, however the aforementioned major Phase I metabolites are the most important from a bioanalysis point of view. Phase II metabolism of the cannabinoids by UDP-glucuronosyltransferases [32] yields more hydrophilic metabolites including THC-glucuronide (THC-glu) and THC-COOH-glucuronide (THC-COOH-glu) from THC ( Figure 1C & D) [24,33] and CBD-glucuronide (CBDglu) and 7-OH-CBD-glucuronide (7-OH-CBD-glu) from CBD ( Figure 2C & D) [34,35]. The major excretion route of THC is via the feces as the conjugated 11-OH-THC and THC-COOH.…”

Section: Disposition and Metabolismmentioning

confidence: 99%

Techniques and Technologies for The Bioanalysis of Sativex ^® , Metabolites and Related Compounds

Molnár

2016

Bioanalysis

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Sativex(®) is an oromucosal spray indicated for the treatment of moderate-to-severe spasticity in multiple sclerosis and is also an effective analgesic for advanced cancer patients. Sativex contains Δ(9)-tetrahydrocannabinol (THC) and cannabidiol in an approximately 1:1 ratio. The increasing prevalence of medicinal cannabis products highlights the importance of reliable bioanalysis and re-evaluation of the interpretation of positive test results for THC, as legal implications may arise in workplace, roadside and sports drug testing situations. This article summarizes published research on the bioanalysis of THC and cannabidiol, with particular focus on Sativex. Common screening and confirmatory testing of blood, urine, oral fluid and hair samples are outlined. Correlations between matrices and current analytical pitfalls are also addressed.

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Distribution of free and conjugated cannabinoids in human bile samples

Cited by 43 publications

References 21 publications

Metabolic patterns of JWH‐210, RCS‐4, and THC in pig urine elucidated using LC‐HR‐MS/MS: Do they reflect patterns in humans?

Metabolic patterns of JWH‐210, RCS‐4, and THC in pig urine elucidated using LC‐HR‐MS/MS: Do they reflect patterns in humans?

In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites

Techniques and Technologies for The Bioanalysis of Sativex ^® , Metabolites and Related Compounds

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Distribution of free and conjugated cannabinoids in human bile samples

Cited by 43 publications

References 21 publications

Metabolic patterns of JWH‐210, RCS‐4, and THC in pig urine elucidated using LC‐HR‐MS/MS: Do they reflect patterns in humans?

Metabolic patterns of JWH‐210, RCS‐4, and THC in pig urine elucidated using LC‐HR‐MS/MS: Do they reflect patterns in humans?

In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites

Techniques and Technologies for The Bioanalysis of Sativex ® , Metabolites and Related Compounds

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Product

Resources

About

Techniques and Technologies for The Bioanalysis of Sativex ^® , Metabolites and Related Compounds