Simple Method for the Determination of THC and THC-COOH in Human Postmortem Blood Samples by Gas Chromatography—Mass Spectrometry
Abstract
:1. Introduction
2. Results and Discussion
3. Materials and Methods
3.1. Chemicals Reagents and Standards
3.2. Specimens
3.3. Analytical Procedure
- Sample pretreatment and liquid-liquid extractionBlood plasma was separated by centrifugation of whole blood when it was possible, and 1 mL of plasma was placed in a screw-capped round bottom glass tube. First, 20 µL methanolic solution of 10 µg/mL of each internal standard (Δ9-THC-D3 and Δ9-THC-COOH-D3) were added. The tube was closed, and its contents mixed. Afterwards, 1 mL of Milli-Q water and 500 µL of 2 M NaOH is added, and the mixture is again stirred. Subsequently, a liquid-liquid extraction was performed with 5 mL of a mixture (9:1, v/v) of hexane-ethyl acetate.The tube is agitated for 10 min to cause the migration of components in the two phases, then it is centrifuged for 10 min, and the organic phase containing the THC is transferred and evaporated to dryness. The dried residue was reconstituted with 40 µL of methanol and injected in the GC-MS system.In order to determine Δ9-THC-COOH, a second extraction is needed starting from the aqueous phase.1 mL of a 0.1 N HCl solution and 200 mL of an acetic acid solution were added, in order to acidify the mixture. Then, it was mixed by agitation for 30 s, and 5 mL of the hexane-ethyl acetate mixture (9:1, v/v) was added again. The tube is agitated for 10 min, centrifuged, and the organic phase transferred to a conical bottom tube with cap and evaporated for later derivatization.The derivatization is carried out by adding a mixture of 40 µL of BSTFA-TCMS (99:1) to the Δ9-THC-COOH dry residue and incubating at 100 °C for 20 min.
- GC-MSGC-MS analyses were performed in an Agilent 6890 Gas Chromatograph equipped with a 7683B automatic liquid sampler, coupled with an Agilent 5973 mass selective quadrupole detector (Agilent Technologies, Las Rozas, Madrid, Spain). The GC injection port was set at 250 °C in splitless mode (purge time 0.75 min). The GC was equipped with an Agilent 19091S-133U 5% phenylmethylsyloxane capillary column, 30 m × 0.25 mm. i.d., 0.50 µm film thickness (purchased by Agilent Technologies, Las Rozas, Madrid, Spain). The oven temperature was held at 90 °C for 1 min, then at 35 °C/min to 200 °C, then at 10 °C/min to 260 °C and held 15 min. Helium was used as carrier gas at a flow of 1 mL/min. The mass detector operated in electron ionization at 70 eV. Initially, a mixture of standards of all the compounds was analyzed in full scan mode (mass range 50–550 amu). Quantifier and qualifier ions used for each analyte were selected based on their abundance and mass-to-charge ratio (m/z). Owing to their reproducibility and lack of interferences, high-mass ions were selected whenever possible. Upon the selection of ions, the mass analyzer was operated in selected ion monitoring (SIM) acquisition mode. All diagnostic ions and retention times are listed in Table 5.
3.4. Method Validation
- Limits of detection, lower limit of quantitation, and specificityThe sensitivity of the method was determined by the calculation of the limit of detection (LOD) and the lower limit of quantitation (LLOQ). LOD was determined by an empirical method that consists of analyzing a series of plasma samples containing decreasing amounts of the analytes. LOD was the lowest concentration that presented a S/N > 3 for at least three diagnostic ions for each substance. The LLOQ was the lowest concentration of analytes in a sample that can be determined with appropriate precision and accuracy. Specificity was studied analyzing 10 negative plasma samples.
- LinearityThe linearity of the method for each compound was studied in the range 0.05–1.5 µg/mL for Δ9-THC and 0.08–1.5 µg/mL for Δ9-THC-COOH, performing 5 extractions and analyses for each level. Calibration curves were built by linear regression of the area ratio of each substance with the internal standard (IS) vs. the concentration of each analyte. Curves with a quadratic regression coefficient (R2) higher than 0.99 were satisfactory.
- Precision and accuracyPrecision, expressed as the coefficient of variation (CV) of the measured values, was expected to be less than 15% at all concentrations, except for the LLOQ for which 20% was acceptable [27]. It was studied on 5 replicate analyses at three levels: 0.1, 0.5, and 1 µg/mL. In the same way, accuracy was evaluated using the mean relative error (MRE), which had to be less than 15% of the theoretical values at each concentration level except for the LLOQ, for which 20% was acceptable [37].
- RecoveryThe recovery of an analyte is the detector response obtained from an amount of the analyte added to and extracted from the biological matrix compared to the detector response obtained for the true concentration of the pure authentic standard [38]. Recovery of the analyte must be optimized to ensure that the extraction is efficient and reproducible. Recovery does not need to be 100%, but the degree of recovery of an analyte and internal standard must be consistent and reproducible. The recovery of the method was examined by comparing the analytical results for extracted samples at 2 levels of concentration (0.1 and 1 µg/mL) 5 times within 3 days versus samples spiked with the standards after the extraction step, where unextracted standards represent 100% recovery.
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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LOD (µg/mL) | LLOQ (µg/mL) | Slope | Intercept | R2 Coef | |
---|---|---|---|---|---|
Δ9-THC | 0.02 | 0.05 | 4.455 | −0.474 | 0.991 |
Δ9-THC-COOH | 0.04 | 0.08 | 1.754 | −0.234 | 0.992 |
Intraday (n = 5) | Interday (n = 5) | ||||
---|---|---|---|---|---|
Concentration (µg/mL) | CV (%) | Relative Mean Error (%) | CV (%) | Relative Mean Error (%) | |
Δ9-THC | 0.1 | 0.43 | 10.14 | 5.71 | 13.45 |
0.5 | 1.08 | 0.65 | 10.30 | 10.10 | |
1 | 2.12 | 7.74 | 1.13 | −3.13 | |
Δ9-THC-COOH | 0.1 | 12.92 | −8.78 | 13.40 | 10.41 |
0.5 | 1.75 | 12.48 | 12.36 | −4.51 | |
1 | 6.58 | 13.80 | 8.87 | −0.12 |
Intraday (n = 5) | Interday (n = 5) | ||||
---|---|---|---|---|---|
Concentration (µg/mL) | Mean Recovery (%) | CV (%) | Mean Recovery (%) | CV (%) | |
Δ9-THC | 0.1 | 82.95 | 10.22 | 83.54 | 5.79 |
1 | 81.51 | 7.28 | 80.69 | 8.28 | |
Δ9-THC-COOH | 0.1 | 95.41 | 3.83 | 94.21 | 4.18 |
1 | 81.01 | 9.81 | 86.12 | 6.82 |
Case Number | Gender | Age | Cause of Death | [Δ9-THC] (µg/mL) | [Δ9-THC-COOH] (µg/mL) | Other Detected Substances |
---|---|---|---|---|---|---|
1 | M | 37 | Traffic Accident | <LLOQ | 0.26 | - |
2 | M | 48 | Drug Overdose | - | 0.28 | Methadone, Benzodiacepines |
3 | M | 50 | Natural Death | - | 0.30 | |
4 | M | 42 | Traffic Accident | - | 0.12 | Ethanol |
5 | M | 42 | Natural Death | - | 0.14 | Ethanol, Paracetamol |
6 | M | 23 | Suicide. Hanging | - | 0.22 | - |
7 | F | 45 | Natural Death | - | 0.83 | - |
8 | M | 23 | Traffic Accident | 0.11 | 0.37 | Ethanol |
9 | M | 40 | Drug Overdose | - | 0.26 | Cocaine, Benzoilecgonine |
10 | M | 53 | Natural Death | 0.12 | 0.53 | Methadone |
11 | M | 46 | Suicide. Hanging | - | 0.17 | - |
12 | M | 52 | Drug Overdose | - | 0.19 | Ethanol, Methadone, Benzodiacepines |
13 | M | 43 | Natural Death | 0.11 | 0.83 | - |
14 | M | 57 | Drowning | - | 0.26 | - |
15 | M | 61 | Drowning | - | 0.32 | - |
16 | M | 40 | Drug Overdose | - | 0.20 | Benzoilecgonine, Citalopram |
17 | M | 48 | Drug Overdose | - | 0.38 | Ethanol, Cocaine, Benzoilecgonine, Methadone |
18 | F | 37 | Drowning | 0.11 | 0.28 | - |
19 | M | 40 | Drug Overdose | 0.12 | 0.22 | Cocaine, Benzoilecgonine |
20 | M | 35 | Suicide. Intoxication | - | 0.16 | Venlafaxine, Cocaine, Benzoilecgonine, Bupropion |
21 | M | 60 | Gas Intoxication | 0.14 | 3.26 | Carboxyhemoglobin |
22 | M | 53 | Natural Death | - | 0.40 | - |
23 | M | 19 | Traffic Accident | - | 3.11 | - |
24 | M | 37 | Suicide. Precipitation | - | 3.38 | Ethanol, Cocaine Benzoilecgonine |
25 | M | 47 | Drug Overdose | 0.11 | 1.77 | Cocaine, Benzoilecgonine |
26 | M | 48 | Drug Overdose | - | 0.65 | Ethanol, Cocaine, Benzoilecgonine |
27 | M | 35 | Drug Overdose | 0.13 | 1.14 | Ethanol, Methadone, Gabapentine |
28 | M | 23 | Traffic Accident | - | 0.43 | Ethanol |
29 | F | 22 | Suicide. Hanging | 0.12 | 0.25 | |
30 | M | 39 | Natural Death | 0.11 | 0.32 | |
31 | F | 18 | Traffic Accident | 0.13 | 1.15 | - |
32 | M | 59 | Drug Overdose | - | 0.15 | Benzodiacepines, methadone, chlometiazole, trazodone |
33 | M | 38 | Suicide. Hanging | - | 0.36 | Cocaine and metabolites |
34 | F | 43 | Drug Overdose | 0.12 | 0.16 | Cocaine and metabolites, methadone |
35 | M | 47 | Traffic Accident | - | 0.37 | - |
36 | F | 18 | Suicide. Precipitation | 0.12 | 0.25 | Ethanol |
37 | F | 38 | Traffic Accident. Pedestrian | - | 0.20 | Ethanol, Cocaine and metabolites |
38 | M | 39 | Drug Overdose | - | 0.50 | Cocaine and metabolites |
39 | F | 42 | Stabbed | - | 0.32 | Ethanol |
40 | M | 60 | Natural Death | 0.17 | 0.21 | - |
41 | M | 44 | Natural Death | - | 0.22 | - |
Retention Time (min) | Quantifier Ion (m/z) | Qualifiers Ions (m/z) | |
---|---|---|---|
THC | 14.80 | 299 | 271, 314 |
THC-D3 | 14.80 | 302 | 274, 317 |
THC-COOH | 20.4 | 371 | 473, 488 |
THC-COOH-D3 | 20.4 | 374 | 476, 491 |
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Álvarez-Freire, I.; Valeiras-Fernández, A.; Cabarcos-Fernández, P.; Bermejo-Barrera, A.M.; Tabernero-Duque, M.J. Simple Method for the Determination of THC and THC-COOH in Human Postmortem Blood Samples by Gas Chromatography—Mass Spectrometry. Molecules 2023, 28, 3586. https://doi.org/10.3390/molecules28083586
Álvarez-Freire I, Valeiras-Fernández A, Cabarcos-Fernández P, Bermejo-Barrera AM, Tabernero-Duque MJ. Simple Method for the Determination of THC and THC-COOH in Human Postmortem Blood Samples by Gas Chromatography—Mass Spectrometry. Molecules. 2023; 28(8):3586. https://doi.org/10.3390/molecules28083586
Chicago/Turabian StyleÁlvarez-Freire, Ivan, Anxa Valeiras-Fernández, Pamela Cabarcos-Fernández, Ana María Bermejo-Barrera, and María Jesús Tabernero-Duque. 2023. "Simple Method for the Determination of THC and THC-COOH in Human Postmortem Blood Samples by Gas Chromatography—Mass Spectrometry" Molecules 28, no. 8: 3586. https://doi.org/10.3390/molecules28083586