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Buy Dibutylone now The number of emerging novel stimulants modified based on beta-keto variations of amphetamine-like substances continues to rise. Dibutylone reports described in the medical and toxicological literature are limited, therefore little information is available in terms of quantitative confirmation or metabolism. During this study,Buy Dibutylone now authentic human specimens, including blood, urine, vitreous humor, oral fluid and liver were quantitatively and qualitatively analyzed for the presence of dibutylone and butylone, with paired case history and demographic information. Dibutylone concentrations were variable across all specimen types, specifically ranging from 10 to 1,400 ng/mL in postmortem blood specimens. The metabolic profile of dibutylone was mapped by in vitro incubation with human liver microsomes (HLM).Buy Dibutylone now Samples were analyzed using a SCIEX TripleTOF® 5600+ quadrupole time-of-flight mass spectrometer. Data processing was conducted using MetabolitePilot™. Authentic human specimens, including blood, urine, vitreous humor, oral fluid and liver, were utilized for in vivo verification of five HLM-generated metabolites in analytically confirmed cases of dibutylone use. Butylone was confirmed as a metabolite of dibutylone, but issues involving co-ingestion of these two novel stimulants or potential co-existence from synthesis lead to ineffectiveness as a true biomarker. Hydrogenation of the beta-ketone of dibutylone resulted in the most prominent metabolite found in human specimens, and its uniqueness to dibutylone over other stimulants leads to its classification as an appropriate biomarker for dibutylone ingestion. This is the first study to map the metabolic profile of dibutylone, including verification in authentic specimens, confirming metabolic conversion to butylone and identifying biomarkers more useful in forensic toxicological drug testing.

Introduction

As with other classifications of novel psychoactive substances (NPS), novel stimulant and novel psychedelic identification and proliferation have been well characterized and monitored throughout recent years (1–3).Buy Dibutylone now Families of novel stimulant drugs based on the cathinone (beta-keto amphetamine) structure, some with hallucinogenic or mood heightening empathogenic, entactogenic or euphoric effects, were among the first waves of NPS identified in Europe in the 2000s (4, 5). While these classes of compounds were originally reported to have less intense effects than traditional stimulant/psychedelic drugs, such as 3,4-methylenedioxymethamphetamine (MDMA) (6), reports of adverse events continue to appear (7), and potency information for these novel compounds is often lacking in human subjects or unavailable (7).Buy Dibutylone now Nonetheless, novel stimulant and psychedelic drugs continue to be identified in toxicological casework on a regular basis, and the most prevalent analyte in these classes changes from year to year (8).

Novel stimulants are referred to by structural classifications, including amphetamine, phenethylamine and cathinone sub-classes (9), however the terminology has significant overlap. There are additional sub-classifications to those previously mentioned, but one of the most popular is the substituted beta-keto-methylenedioxyamphetamines, whose popular names end in “-lone” and include methylone, dimethylone, ethylone, butylone, pentylone and others (Figure 1). This beta-keto sub-class dates back to the synthesis of methylone in the 1950s (10) and patents filed in the 1960s (11) including dibutylone, pentylone, eutylone and N-ethyl pentylone (ephylone). Many years later in the mid-1990s, methylone (bk-MDMA) was nicknamed by Peyton Jacob III and Alexander Shulgin (12). Over half a century after its synthesis, methylone was identified in the street drug supply being substituted and/or sold for recreational purposes to circumvent illegality of MDMA and other traditional stimulants (5), leading to the proliferation of methylone and its analogs in recent years, up to and including seizures of dibutylone in the United States in 2016 (13, 14).

Figure 1.
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Structures of novel stimulants and MDMA.

Following the appearance of methylone,Buy Dibutylone now a succession of novel stimulants was seen including butylone beginning in 2012 (15, 16), ethylone in 2014 (17, 18) and dibutylone in 2016 (13, 14). Dibutylone (Figure 1), known as beta-keto-dimethylbenzodioxolylbutanamine, bk-DMBDB, bk-MMBDB or methylbutylone, is one of the more recent novel stimulants in this series to be reported in forensic toxicology casework and the street drug supply.Buy Dibutylone now The first mention of dibutylone came in a 1967 patent, alongside other now emerging novel stimulants (11). Dibutylone was first reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) by Finland in 2010 (19), but more detailed information was not available until 2014 when tablets were seized and positively identified in Sweden (20). In the United States, dibutylone was not reported until 2016 (13), by which time it had become the fourth most commonly detected phenethylamine drug in the country and most commonly detected novel phenethylamine, overtaking ethylone from 2015, according to data generated by the National Forensic Laboratory Identification System (NFLIS). As of 2016, dibutylone was still reported as the most commonly detected novel phenethylamine (14).

Currently, Buy Dibutylone now there are limited reports in the literature involving intoxications or deaths with these beta-keto-methylenedioxyamphetamines, as many laboratories do not routinely test for them, and their specific toxicity profile is unknown (7). Pharmacological and toxicological effects of dibutylone have not been previously reported, although it has been proposed that its effects and adverse events would be similar to previously described novel stimulants (21). One possible comparison is to butylone toxicity (15). In this case described as serotonin syndrome, resulting from the ingestion of an “Ecstasy” pill containing butylone and methylone, hospital personnel reported tachycardia, tachypnea, and hypertension and the patient experienced diaphoresis, tremors and hyperreflexia. The patient was aggressively cooled, but due to multi-system organ failure eventually died. In another case of attempted suicide following ingestion of 10 butylone tablets, hospital personnel report tachycardia, hypertension, increased muscle tonus, hypersalivation, mydriasis and hyperthermia, in addition to noted arrhythmias (22). Butylone is also reported to cause hyperventilation and prominent behavioral changes (23).

To better assist laboratories and toxicologists in the identification and interpretation of NPS use and drug positivity,Buy Dibutylone now   it is important to understand novel stimulant metabolic fate as the identification of metabolites can prolong detection windows. Furthermore, due to the structural relationships between the members of the beta-keto methylenedioxyamphetamine drug class, many novel stimulants are metabolized into another biologically active novel stimulant (8, 24–26), which can create scenarios where multiple drugs are contributing to effects.

This manuscript reports analytical methods for the identification and quantitation of dibutylone and its in vitro metabolic products, and confirmation of these metabolites in authentic human biological specimens from dibutylone intoxications.

Methods

Chemicals and reagents

Butylone and dibutylone were purchased from Cayman Chemical (Ann Arbor, MI, USA). Reference material was prepared at 1 mg/mL in methanol. Diazepam (1 mg/mL) was purchased from Cerilliant (Round Rock, TX, USA). Nicotinamide adenine dinucleotide phosphate (NADPH) was purchased from Cayman and used as the cofactor during human liver microsome (HLM) incubations.Buy Dibutylone now  Sodium phosphate was purchased from Sigma-Aldrich (St. Louis, MO, USA) to prepare a buffer solution at 100 mM (pH 7.4) with addition of magnesium chloride (Sigma-Aldrich) at 10 mM.

All solvents and reagents, of LCMS grade purity, used during sample preparation and instrumental analysis were purchased from Honeywell (Morris Plains, NJ, USA). Pooled HLMs (20 mg/mL, 50 donors) were purchased from ThermoFisher Scientific (Waltham, MA, USA) and stored at −80°C. Sodium borate decahydrate was purchased from EMD Millipore Corporation (Darmstadt, Germany) for preparation of Borax buffer.

Dibutylone confirmation and quantitation

NMS Labs (Willow Grove, PA, USA) provided discarded postmortem blood (n = 9), urine (n = 4), vitreous humor (n = 1) and liver (n = 1) specimens from death investigation toxicology casework (n = 9) that had previously tested positive for dibutylone. Specimens were collected between January 2016 and July 2017. Personal identifiers were removed from any specimens or case histories before being provided.Buy Dibutylone now  Case circumstances, when available, were tabulated and are provided in Table I (Case 1–9). Specimens were extracted using solid phase extraction (Agilent Bond Elut Plexa PXC, 3 mL, 30 mg).Buy Dibutylone now   The extraction cartridges were conditioned with acetonitrile and water, the sample was applied and washed with hydrochloric acid in water (0.1 N) and acetonitrile, and the sample was eluted using a mixture of water, acetonitrile and ammonium hydroxide (55:40:5, v-v:v).

Table I.

Case information for biological specimens and quantitative confirmation

CaseAgeSexCase HistoryDibutylone Concentration (ng/mL)Butylone Concentration (ng/mL)Other Findings (ng/mL unless otherwise noted)
132FIndividual found deceased in bed; drug overdose suspected.
  • Femoral Blood: 383

  • Urine: 3,100

  • Vitreous Humor: 250

  • Liver: Positive

  • Femoral Blood: 92.5

  • Urine: 69.7

  • Vitreous Humor: 108

  • Liver: Positive

Femoral Blood: THC (2.8), THC-COOH (11)
246MIndividual found deceased in hotel room.
  • Femoral Blood: <10

  • Urine: 16,500

  • Femoral Blood: 385

  • Urine: 3,060

Femoral Blood: Alprazolam (110), Benzoylecgonine (1, 600), Hydrocodone (400), Oxycodone (13), Tramadol (340)
338MIndividual involved in fatal motor vehicle crash.
  • Femoral Blood: 61.5

  • Urine: 2,140

Femoral Blood: 6.55Urine: 149
  • Femoral Blood: Ethanol (190 mg/dL), 4-Fluoroamphetamine, Methylone (31), Dimethylone, Ethylone (<10)

  • Urine: Ethylone (269)

4FSuspected drug overdoseFemoral Blood: 1,400Femoral Blood: 600
549MSuspected use of “bath salts”Femoral Blood: 10NDFemoral Blood: 4-Chloro-alpha-PVP
6MUnknownCentral Blood: 11ND
7MUnknownFemoral Blood: 13Blood: 12
8MAlleged “molly” usePostmortem Blooda: 14ND
9FSuspected drug overdosePostmortem Blooda: 40Postmortem Blood: 15.3Postmortem Blood: Para-fluoroisobutyrylfentanyl
1037MSample collected at an electronic dance music festival. History of recreational drug use. Indicated use of “MDMA.” Took three (3) capsules within 24 hours of samples collection.Oral Fluid: 123.2Oral Fluid: 206.2Oral Fluid: Dimethylone, MDMA, MDA
1122MSample collected at an electronic dance music festival. History of recreational drug use. Indicated use of “MDMA.” Took two (2) capsules within 24 hours of samples collection.Oral Fluid:137.6Oral Fluid:291.3Oral Fluid: Dimethylone, MDMA, MDA
12Sample collected at an electronic dance music festival. Additional information unknown.Oral Fluid:1926.2Oral Fluid:1761.4Oral Fluid: Dimethylone, MDMA, MDA
1329MSample collected at an electronic dance music festival. No indication of stimulant use.Oral Fluid: PositiveOral Fluid: Positive
1418FSample collected at an electronic dance music festival. History of recreational drug use. Took two (2) “Molly” within 24 hours of samples collection.Oral Fluid: PositiveOral Fluid: Positive
1526MSample collected at an electronic dance music festival. Additional information unknown.Oral Fluid: PositiveOral Fluid: PositiveOral Fluid: Cocaine

 Postmortem blood type not indicated.

ND, none detected; (–) No additional findings reported.

 

Quantitative confirmatory analysis in blood and urine for butylone and dibutylone was performed using a Waters TQD tandem mass spectrometer coupled with a Waters Acquity ultra performance liquid chromatograph (LC–MS-MS), an analytical method validated according to the Scientific Working Group for Forensic Toxicology (SWGTOX) Standard Practices for Method Validation in Forensic Toxicology (27). Performance characteristics included bias, precision, linearity, limit of detection, limit of quantitation,Buy Dibutylone now  dilution integrity, stability, and evaluation of interferences and carryover, with all values within acceptable criteria. Matrix types for which comprehensive validation had not been performed (i.e., vitreous humor, liver) were analyzed using the method of standard addition (28, 29). This approach utilized three separate aliquots of the specific case specimen, to which standard drug solution in increased amount (i.e., 10 ng/mL and 100 ng/mL) was added to only two of these specimens. The concentration of drug solution added was determined based on an estimated case specimen concentration. The final concentration was calculated (y-intercept) using a linear regression by plotting peak area ratio and standard addition blank and spiked concentrations (i.e., 0, 10 and 100 ng/mL).

In addition to specimens from authentic forensic casework, human oral fluid specimens were collected (March 2016 and March 2017) using the Quantisal™ oral fluid collection device (Immunalysis, Pomona, CA, USA) from volunteer drug-using subjects as part of a larger Institutional Review Board approved study (Arcadia University, Glenside, PA, USA) to evaluate trends in novel stimulant and NPS use among dance music festival attendees. Buy bk-DMBDB near me Samples included in this assessment had previously tested positive for dibutylone using a previously described and validated liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF) screening method (8). Case information is provided in Table I (Case 10–15). Samples were prepared for analysis by liquid–liquid extraction using borax buffer (0.1 M, pH 10.4) and N-butyl chloride/ethyl acetate (70:30, v:v).

Table II.

Identification of dibutylone metabolites using HLMs

IDBiotranformationFormula[M + H]+ (Da) Theoretical[M + H]+ (Da) ExperimentalMass Error (ppm)Average Retention Time (min)Average Peak AreaAccurate Fragment Mass (Da)
Parent(Dibutylone)C13H17NO3236.1281236.1276−2.44.311.18E+06
  • 191.0691

  • 161.0587

  • 149.0225

  • 133.0645

  • 121.0278

  • 86.0974

M1HydrogenationC13H19NO3238.1438238.14411.24.222.09E+04
  • 220.1333

  • 191.0937

  • 135.0438

  • 117.0698

  • 86.0976

M2DemethylenationC12H17NO3224.1281224.12841.22.911.87E+05
  • 179.0697

  • 161.0593

  • 137.0230

  • 123.0439

  • 109.0284

  • 86.0979

M3Demethylenation, HydrogenationaC12H19NO3226.1438226.1432−2.71.767.18E+02
  • 208.1327

  • 179.0934

  • 145.0640

  • 123.0442

M4Demethylation(Butylone)C12H15NO3222.1125222.1122−1.24.232.11E+05
  • 204.1008

  • 191.0697

  • 174.0891

  • 149.0227

  • 131.0722

  • 72.0826

M5Di-demethylationaC11H13NO3208.0968208.0962−3.24.071.17E+03
  • 160.0756

  • 149.0245

  • 132.0805

  • 121.0277

  • 58.0667

aMetabolites only identified in two incubation mixtures, identified in authentic specimens.

 

Quantitative confirmatory analysis for butylone, dibutylone, methylone, dimethylone, ethylone, pentylone, N-ethyl pentylone, eutylone, MDMA and MDA was performed using an Agilent 6430 tandem mass spectrometer coupled with an Agilent 1100 series high performance liquid chromatograph (LC-MS/MS),Buy bk-DMBDB near me an analytical method validated according to guidelines set forth by SWGTOX (27). Performance characteristics included bias, precision, linearity, limit of detection, limit of quantitation, dilution integrity, stability, and evaluation of interferences and carryover, with all values within acceptable criteria.

HLM incubations

Microsomal incubations were conducted according to previously published methods (30) for the identification of phase I metabolic transformations.Buy bk-DMBDB near me HLM incubation mixtures containing phosphate buffer (520 μL, 100 mM, pH 7.4), dibutylone or diazepam (5 μL, 1 mg/mL in 50:50 buffer:acetonitrile), NADPH (50 μL) and HLMs (25 μL, 20 mg/mL, 50 donors) were prepared in duplicate alongside single standard and reagent control mixtures containing drug standard or drug standard and HLMs only, respectively.Buy bk-DMBDB near me These sample types were prepared over 3 days, for a total of six metabolism incubation mixtures. Incubations were performed at 37°C for 2 h. Diazepam was used as a batch metabolic control during the study to verify the activity of the microsomes.Buy bk-DMBDB near me Following incubation, simple sample cleanup, using centrifugation and membrane filters, was performed prior to analysis by LC-QTOF.

LC-QTOF analysis

Data was acquired using a SCIEX (Framingham, MA, USA) TripleTOF® 5600+ QTOF coupled with a Shimadzu (Kyoto, Japan) Nexera XR ultra high performance liquid chromatograph. Ammonium formate (10 mM, pH 3) and methanol/acetonitrile (50:50) were used in a linear gradient (95:5 to 5:95) at a flow rate of 0.4 mL/min.Buy bk-DMBDB near me  A Phenomenex® Kinetex C18 analytical column (50 mm × 3.0 mm, 2.6 μm) was used to achieve chromatographic separation. The total run time was 15.5 min.

Mass acquisition was performed using data independent (SWATH®) and data dependent (IDA) QTOF acquisition modes (30). Source conditions were identical with ionization by positive electrospray.Buy bk-DMBDB near me  Both acquisition modes generate accurate mass precursor ion (TOF MS) and accurate mass fragment ion (MSMS) data for formula and structural elucidation of metabolites formed during the incubations. Precursor ion fragmentation was achieved using a collision energy spread (35±15 eV), resulting in a range of low and high molecular weight product ions.

Software and data processing

Data files were processed using MetabolitePilot™ (SCIEX, Version, 1.5), PeakView® (SCIEX, Version 2.2) and MasterView™ (SCIEX, Version 1.1). Potential metabolites were identified based on precursor and product ions, confirmed using reference material (when available), and verified in authentic human toxicological specimens (previously described) which had previously tested positive for dibutylone.

Initial metabolite identification and determination of their proposed structures were created using MetabolitePilot™ using the data files acquired via IDA. The identities of the metabolites were verified by investigating both IDA and SWATH® acquired data in PeakView®, while additionally identifying any further metabolites which had not been identified during MetabolitePilot™ processing. An extracted ion chromatogram (XIC) list was generated containing metabolite name, formula, accurate mass and retention time.Buy bk-DMBDB near me  Metabolite MSMS spectra were added to an in-house library database for evaluation of the presence of these in vitro metabolites in authentic specimens.

Authentic biological specimens for metabolite confirmation

The previously mentioned blood, vitreous humor, liver, oral fluid specimens were prepared for metabolite confirmatory analysis by single-step liquid–liquid extraction using Borax buffer (10 mM, pH 9.6) and an N-butyl chloride/ethyl acetate (80:20) mixture.Buy bk-DMBDB near me  Urine samples were hydrolyzed via an enzymatic process with beta-glucuronidase (Sigma-Aldrich) and incubated at 50°C for one hour prior to extraction. Following centrifugation and removal of the aqueous layer, 10% HCl in methanol (100 μL) was added to the organic layer for evaporation under nitrogen at 35°C.

Sample extracts were analyzed using the same LC-QTOF method described above via SWATH® acquisition. The resulting data files were processed using MasterView™, software for broad-based drug screening procedures to identify sample components based on previously established XIC lists.Buy bk-DMBDB near me  The presence of the proposed metabolites in the authentic specimens was evaluated based on the following criteria: mass error (<10 ppm); retention time error (<0.35 min); isotope difference (<50%); library score (>70); signal-to-noise ratio (>10); and peak shape and intensity.

Results and Discussion

Dibutylone confirmation and quantitation

Quantitative and qualitative confirmation of dibutylone and butylone in these populations is shown in Table I. Buy bk-DMBDB near me All cases analyzed during this study had one specimen positive for at least dibutylone. Ten of the individuals were male, four were female and one gender was not listed. The average age (± standard deviation) across these dibutylone-using populations was 33 (±10.4) years (median 32 years). In blood specimens collected during death investigation,Buy bk-DMBDB near me the average dibutylone concentration was 241 (±484) ng/mL, the median was 27 ng/mL and the range was 10–1,400 ng/mL. For butylone in these same blood specimens, the average concentration was 228 (±257) ng/mL, the median was 130 ng/mL and the range was <10–600 ng/mL. It is interesting that dibutylone was found in conjunction with other novel stimulants and NPS within these individuals, including the more traditional stimulant MDMA.

Table I includes additional findings as reported by NMS Labs following case-dependent testing or by CFSRE following comprehensive testing for research purposes, both of which include the confirmation of various NPS classes. These findings are those that were reported in addition to dibutylone positive results, and were contingent on screening results, client requests and/or case leads. Not all specimens were analyzed using the same directed approach, but all results were confirmed.

Analysis of dibutylone incubation mixtures

Analysis of data from LC-QTOF analysis of the incubation mixtures resulted in the identification of five metabolites of dibutylone (Figure 2). Characteristic common accurate mass fragment ions were identified among and between the proposed metabolites. Experimental data consisting of accurate precursor ion mass, formula, retention time and accurate product ion masses was tabulated (Table II). Metabolites identified were classified as “unique”, i.e., structurally dissimilar to other related NPS stimulants and their metabolites, and “common”, i.e., those similar or identical in their mass spectral characteristics to other novel stimulants and their metabolites. Buy Dibutylone now

Figure 2.
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Metabolic pathway of dibutylone including fragmentation pattern.

Unique metabolites

Dibutylone was found to undergo hydrogenation of the beta-ketone species producing M1, 1-(1,3-benzodioxol-5-yl)-2-(dimethylamino)butan-1-ol (Figure 2). M1 exhibited a protonated ion of 238.1438 Da at a retention time of 4.22 min (Table II). The most prominent fragment ion, 191.0937 Da, differed from that of dibutylone, 149.0225 Da (Figure 3), as the result of the reduction of the ketone and absence of the formation of the acylium ion. This metabolite was determined to be unique to dibutylone, however other positional isomers of dibutylone could metabolize to a species with the same molecular formula and exact mass. Buy Dibutylone now

Figure 3.
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MS/MS spectra of parent dibutylone (top), M1 (middle) and M2 (bottom).Buy bk-DMBDB near me

Demethylenation of dibutylone resulted in the formation of M2, 1-(3,4-dihydroxyphenyl)-2-(dimethylamino)butan-1-one (Figure 2). M2 exhibited a protonated ion of 224.1284 Da at a retention time of 2.91 min (Table II). The most prominent fragment ion, 137.0230 Da, differed from that of dibutylone, 149.0225 Da (Figure 3), due to loss of the carbon atom associated with the methylenedioxy-bridge and formation of the acylium ion. Like M1, M2 was determined to be unique to dibutylone, Buy bk-DMBDB near mehowever other positional isomers of dibutylone could metabolize to a species with the same molecular formula and exact mass.

A combination of the previous two biotransformations (hydrogenation and demethylenation) result in the formation of M3, 4-[2-(dimethylamino)-1-hydroxy-butyl]benzene-1,2-diol (Figure 2). M3 exhibited a protonated ion of 226.1432 Da at a retention time of 1.76 min (Table II). The fragmentation associated with this metabolite differed from dibutylone, M1 and M2. M3 was a minor product of incubation, and was identified in only two of the six incubation mixtures.

Common metabolites

When core structures are modified to create new drugs, Buy Dibutylone now different substances can form common metabolites if they retain the necessary structural elements. Identification of these common metabolites in casework samples can be useful in indicating the class of substance ingested, even if the identity of the parent is initially unknown. In addition, ingestion of more than one substance must also be considered when a common metabolite is also a known NPS. The common metabolic processes of O– and N-demethylation of drugs including isomers of the beta-keto-methylenedioxyamphetamines can lead to the formation of common metabolites, depending on the positioning of (in this case) the methyl-substituent. For example, identification of both butylone and dibutylone together could be a result of either co-ingestion of the two drugs, or butylone being a metabolite of dibutylone.

HLM incubations of dibutylone demonstrated N-demethylation to form butylone (M4, Figure 2). Butylone exhibited a protonated ion of 222.1122 Da at a retention time of 4.23 min (Table II). The most prominent fragment ions were 174.0891 and 175.0616 Da. The identity of this metabolite as butylone was achieved based on its identical (MSMS) library spectral entry and retention time. Butylone was thus confirmed as a metabolite of dibutylone for the first time using this approach, and is consistent with the metabolism of dimethylone to methylone (8).Buy bk-DMBDB near me

Butylone (M4) was found to further transform through N-demethylation resulting in M5, N-desmethyl-butylone or 2-amino-1-(1,3-benzodioxol-5-yl)butan-1-one (Figure 2). M5 exhibited a protonated ion of 208.0962 Da at a retention time of 4.07 min (Table II). The most prominent fragment ion was 160.0756 Da. This metabolite (M5), or N-desmethyl-butylone, has been previously characterized for butylone (24) and is thus a common metabolite of dibutylone and butylone.

Authentic human specimens

All five metabolites of dibutylone (M1–M5) characterized during HLM incubations were identified in the authentic specimens collected from subjects that had previously tested positive for dibutylone (Table III). The relative percentage of each metabolite found in the sample is represented as a percentage of the base peak. To calculate these values, precursor ion intensities were divided by the largest metabolite ion intensity in that specimen. Dibutylone was identified in all specimens analyzed during this study.

Table III.

Dibutylone and metabolites identified in authentic human specimens (% base peak)

Case #MatrixDibutyloneM1M2M3Butylone (M4)M5
1Blood78.7100NDND5.2LR
Urine65.3100NDNDND0.1
Vitreous60.0100NDLR4.8LR
Liver68.8100ND>0.16.20.5
2Blood10050.50.1ND5.60.1
Urine10055.60.1>0.19.40.2
3Blood10038.0NDND7.3ND
Urine10018.8NDND4.9ND
10Oral Fluid33.5100NDLR17.6LR
11Oral Fluid29.5100NDLR17.6LR
12Oral Fluid98.9100NDLR14.90.2
13Oral Fluid100LRNDNDLRND
14Oral Fluid10060.5NDND26.6ND
15Oral Fluid10029.9NDND24.6ND

ND, not detected; LR, low response.

Issues can arise when metabolic pathways and potential organic synthesis pathways overlap, leading to decreased certainty and specificity in determining drug use based on metabolites identified. Ultimately, toxicological testing of biological specimens collected without true certainty of drug use can lead to uncertainty in determination of co-ingestion or metabolic generation. M1 was consistently the most prominent metabolite in all specimen types. This is significant due to its uniqueness to the parent and specificity in determining dibutylone ingestion. Butylone (M4) was identified as the second most prominent metabolite, but a determination as to whether all the butylone derived from metabolism in these subjects cannot be made. Therefore, M1 is more appropriately characterized as a specific biological marker for dibutylone ingestion.Buy bk-DMBDB near me

Knowledge about tissue distribution of dibutylone and butylone are helpful for postmortem interpretation, as not all matrices are available in every case. M2 was only identified in one of the postmortem cases, highlighting the possibility of intra-individual metabolic variation. M3 and M5 were often found at much lower relative intensities in the authentic specimens compared to the other metabolites, underscoring their status as minor metabolites.

Buy Dibutylone now  Conclusions

Intoxications involving dibutylone with accompanying quantitative confirmation have been described, providing data for toxicologists on relative concentrations of dibutylone and the presence of its metabolite, butylone. The metabolic profile of dibutylone was characterized using HLM incubations and the presence of these metabolites was confirmed in authentic Buy Dibutylone now human specimens from living and deceased individuals by LC-QTOF analysis.

In total, five metabolites of dibutylone were identified in prepared incubation samples, and confirmed in authentic human specimens. Butylone (M4) was identified as the most abundant metabolite during microsomal incubations, however it was not possible to determine whether butylone was the result of metabolism or co-ingestion in the authentic specimens. M1 was identified as the primary metabolite during analysis of authentic specimens, and serves as a more appropriate biomarker in the absence of the parent compound, than butylone (M4) for ingestion based on uniqueness to dibutylone. Standard reference materials for the unique dibutylone metabolites (M1-M3) and the common butylone/dibutylone metabolite (M5) are currently unavailable. Structural identification of metabolites in this study were based on review of mass spectral data and procedures to assist with structural elucidation. Dibutylone was identified in all human specimens from cases analyzed and described in Table I. This knowledge of metabolites can help prolong the detection window in biological matrices after dibutylone intoxications; however, confirmation of these metabolites requires synthesis of reference material for analytical comparison in order to meet the forensic burden of proof.Buy bk-DMBDB near me

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