Subacute Toxicity and Pharmacokinetic Evaluation of the Synthetic Cannabinoid 4F-MDMB-BUTINACA in Rats: A Forensic and Toxicological Perspective
Abstract
1. Introduction
2. Materials and Methods
2.1. Drug Preparation and Animals
2.2. Chemicals and Reagents
2.3. Preparation of the Calibrators and QC Samples for GC-MS Validation
2.4. Procedures of Liquid–Liquid Extraction of the Drug from the Plasma
2.5. Validation of GC–MS/MS Analysis
2.5.1. Evaluation of the GC–MS/MS Selectivity
2.5.2. Evaluation of the GC–MS/MS Sensitivity
2.5.3. Evaluation of the GC–MS/MS Linearity
2.5.4. Evaluation of the GC–MS/MS Accuracy and Precision
2.5.5. Evaluation of the Method’s Recovery and Stability
2.6. Animal Experiments for Evaluating the Pharmacokinetic Profile
2.6.1. Calculations of the Pharmacokinetic Parameters
2.6.2. Statistical Analysis
2.7. Animal Experiments for Evaluating the Sub-Acute Toxicity
2.7.1. Hematological Parameters
2.7.2. Biochemical Parameters
2.7.3. Histopathology
3. Results and Discussions
3.1. GC–MS/MS Method Suitability for Routine Analysis
3.2. Pharmacokinetic Profile of 4F-MDMB-BUTINACA Following Oral Administration at a Dose of 50 mg/kg
3.3. Monitoring the Sub-Acute Toxicity of the 4F-MDMB BUTINACA on the Studied Animals
3.4. Hematological Changes with 4F-MDMB BUTINACA Oral Administration
3.5. Serobiochemical Changes with 4F-MDMB BUTINACA Oral Administration
3.6. Diagnosis of the Subacute Toxicity of 4-MDMB-Butinaca and Histopathological Changes
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Abbreviation | Meaning |
°C | Degree Celsius |
4F-Binaca | N-[[1-(4-fluorobutyl)-1H-indazol-3-yl]carbonyl]-3-methyl-L-valine, methyl ester |
4F-MDMB-BUTINACA | N-[[1-(4-fluorobutyl)-1H-indazol-3-yl]carbonyl]-3-methyl-L-valine, methyl ester |
ALB | Albumin |
ALP | Alkaline phosphatase |
ALT | Alanine aminotransferase |
AST | Aspartate aminotransferase |
BC | Bowman’s capsule |
Bias% | Accuracy |
BS | Bowman’s space |
Ca | Calcium |
CE | Collision energy (mass spectroscopy) |
CHOL | Total cholesterol |
Cl | Clearance |
DBIL | Direct bilirubin |
DMSO | Dimethyl sulfoxide |
DT | Distal tubule |
El | Electron ionization technic |
eV | Potential energy/electric vehicle |
FDA’s | Food and Drug Administration |
G | Dlomerulus |
GC-MS | Gas chromatographic–mass spectrometric |
GGT | Gamma-glutamyl transferase |
H&E | Hematoxylin and eosin stain |
HDL | High-density lipoprotein |
HQC | High-quality control |
IS | Internal standard |
K | Elimination rate |
LC–MS | Liquid chromatography–mass spectrometry |
LC–MS/MS | Liquid chromatography with tandem mass spectrometry |
LOD | Limit of detection |
LOQ | Limit of quantitation |
LQC | Low-quality control |
m/z | Mass-to-charge ratio |
Min | Minutes |
MQC | Medium-quality control |
MS | Mass spectrometry |
OECD | Organization for Economic Cooperation and Development |
PHOS | Phosphate |
PT | Proximal tubule |
QC | Quality control |
r2 | Correlation coefficient |
RSD | Relative standard deviation |
RSD% | Precision |
RT | Retention time |
SCs | Synthetic cannabinoids |
SIM | Selected ion monitoring |
t1/2 | Half-life |
TBIL | Total bilirubin |
TG | Triglycerides |
THC | Tetrahydrocannabinol |
TP | Total protein |
UCT | United Chemical Technologies |
Vd | Volume of distribution |
WBC | White blood cell count |
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Temp. Gradient °C/min | Temperature °C | Hold Time min | Run Time min |
---|---|---|---|
- | 150 | 2 | 0.5 |
30 | 320 | 5.3333 | 13 |
Compound | Retention Time (min) | Quantifier Transition Ion | Collision Energy (eV) | Qualifier Transition Ions | Collision Energy (eV) | ||
---|---|---|---|---|---|---|---|
4−Fluoro MDMB−BUTINACA | 8.149 | 364 | 304 | 20 | 364 | 345 | 20 |
364 | 219 | ||||||
Granisetron (IS) | 9.550 | 313 | 176 | 12 | 313 | 126 | 12 |
313 | 96 |
Plasma Concentration (ng/mL) | Mean Recovery Concentration (ng/mL) | SD | RSD% | Bias |
---|---|---|---|---|
<15% | ±<15% | |||
10 | 9.372 | 0.236 | 2.52 | −6.28 |
100 | 95.586 | 2.466 | 2.58 | −4.41 |
500 | 498.248 | 8.207 | 1.647 | −0.35 |
Expected | QC1-10 ng/mL | QC2-100 ng/mL | QC3-500 ng/mL |
---|---|---|---|
Day 1 | 9.372 | 95.586 | 498.248 |
Day 2 | 9.35 | 97.05 | 487.804 |
Day 3 | 9.62 | 97.742 | 489.66 |
Mean | 9.447 | 96.793 | 491.904 |
S.D. | 0.150 | 1.101 | 5.572 |
RSD% | 1.587 | 1.137 | 1.133 |
Bias% | −5.527% | −3.207% | −1.619% |
Post-administration time (hours) | 0.5 (n = 6) | 1 (n = 6) | 2 (n = 6) | 4 (n = 4) | 6 (n = 1) |
Mean plasma concentration in (ng/kg) for oral administeration of 50 mg/kg of the substance | 23.557 | 28.64 | 41.135 | 87.18 | 110.371 |
Log10 for dose 50 mg/kg | 1.372 | 1.457 | 1.614 | 1.940 | 2.043 |
Intercept | 1.3424 |
Slope | 0.1269 |
C0 | 21.99885109 ng/kg |
K | 0.2922507 h−1 |
Dose | 50,000,000 ng/kg |
Vd | 2272.85 L |
t1/2 | 2.371 h. |
Cl | 664.241 L/h |
AUC | 75.2739 ng·h/mL |
Parameters | Control (n = 6) | 4F-MDMB-BUTINACA (1 mg/kg/Day) (n = 6) | 4F-MDMB-BUTINACA (5 mg/kg/Day) (n = 6: 3 Survived, 3 Died) |
---|---|---|---|
WBC | 3.8 ± 0.47 | 2.67 ± 0.26 | 2.00 ± 0.32 |
RBC | 6.82 ± 0.33 | 7.30 ± 0.28 | 7.18 ± 0.38 |
HGB | 13.17 ± 0.34 | 13.40 ± 0.56 | 13.60 ± 0.32 |
HCT | 42.93 ± 2.8 | 47.43 ± 2.5 | 43.87 ± 0.58 |
MCV | 63.07 ± 1.7 | 65.43 ± 6 * | 61.40 ± 2.9 * |
MCH | 19.33 ± 0.58 | 18.37 ± 0.9 | 19 ± 0.6 |
MCHC | 30.70 ± 0.41 | 28.50 ± 2.5 * | 31 ± 0.76 * |
RDW | 18.10 ± 0.5 | 22.17 ± 5.1 * | 19.57 ± 0.9 * |
PLT | 748.33 ± 49 | 824.67 ± 19 * | 789.67 ± 7.4 * |
NE | 0.13 ± 0.13 | 0.05 ± 0.001 * | 0.33 ± 0.06 * |
LY | 2.33 ± 0.3 | 2.30 ± 0.2 | 1.60 ± 0.32 |
ES | 0.33 ± 0.033 | 0.001 ± 0.011 * | 0.001 ± 0.01 * |
BA | 0.33 ± 0.033 | 0.001 ± 0.012 * | 0.067 ± 0.66 * |
Parameters | Control (n = 6) | 4F-MDMB-BUTINACA (1 mg/kg/Day) (n = 6) | 4F-MDMB-BUTINACA (5 mg/kg/Day) (n = 6: 3 Survived, 3 Died) |
---|---|---|---|
AST (U/L) | 115.65 ± 2.1 | 145.18 ± 3.3 * | 146.1 ± 1.2 * |
ALT (U/L) | 64.28 ± 0.43 | 75.8 ± 9.1 * | 78.06 ± 6.7 * |
GGT (U/L) | 45.6 ± 3.7 | 56.43 ± 2.2 * | 46.18 ± 1.4 * |
ALP (U/L) | 562.03 ± 16.4 | 623.32 ± 14 | 591.5 ± 17.5 * |
HDL (mmol/L) | 1.47 ± 0.1 | 1.14 ± 0.04 | 1.21 ± 0.07 |
LDH (U/L) | 238.4 ± 5.4 | 392.9 ± 57.2 | 204.28 ± 9.1 |
CHOL (mmol/L) | 2.26 ± 0.2 | 1.85 ± 0.2 | 1.88 ± 0.05 |
TG (mmol/L) | 0.81 ± 0.07 | 0.93 ± 0.31 * | 0.92 ± 0.2 |
TBIL (umol/L) | 1.523 ± 0.44 | 2.5 ± 0.02 * | 2.32 ± 0.1 * |
DBIL (umol/L) | 0.157 ± 0.1 | 0.27 ± 0.03 | 0.5 ± 0.1 |
TP (g/L) | 61.1 ± 0.31 | 55.21 ± 1.4 * | 60.7 ± 0.5 * |
ALB (g/L) | 32.3 ± 0.14 | 29.51 ± 1.2 * | 32.75 ± 0.92 * |
UREA (mmol/L) | 5.84 ± 0.5 | 5.36 ± 0.6 | 8.95 ± 0.26 * |
Na (mmol/L) | 140.9 ± 0.2 | 139.88 ± 0.52 | 142.4 ± 0.75 |
K (mmol/L) | 5.36 ± 0.14 | 5.12 ± 0.5 | 4.76 ± 0.17 |
CL (mmol/L) | 99.03 ± 0.9 | 97.24 ± 1.8 | 101.33 ± 1 |
PHOS (mmol/L) | 3.24 ± 0.8 | 3.147 ± 0.1 | 2.5 ± 0.3 |
IRON (umol/L) | 43.5 ± 6.5 | 33.38 ± 5.8 | 58.15 ± 18 |
Ca (mmol/L) | 3.057 ± 0.05 | 3.1 ± 0.05 | 2.73 ± 0.6 |
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Abdelgadir, E.H.; Al-Qudsi, J.; Abu-Nukhaa, E.S.; Alsidrani, D.A. Subacute Toxicity and Pharmacokinetic Evaluation of the Synthetic Cannabinoid 4F-MDMB-BUTINACA in Rats: A Forensic and Toxicological Perspective. Future Pharmacol. 2024, 4, 676-699. https://doi.org/10.3390/futurepharmacol4040036
Abdelgadir EH, Al-Qudsi J, Abu-Nukhaa ES, Alsidrani DA. Subacute Toxicity and Pharmacokinetic Evaluation of the Synthetic Cannabinoid 4F-MDMB-BUTINACA in Rats: A Forensic and Toxicological Perspective. Future Pharmacology. 2024; 4(4):676-699. https://doi.org/10.3390/futurepharmacol4040036
Chicago/Turabian StyleAbdelgadir, Elkhatim Hassan, Jihad Al-Qudsi, Elham S. Abu-Nukhaa, and Dimah A. Alsidrani. 2024. "Subacute Toxicity and Pharmacokinetic Evaluation of the Synthetic Cannabinoid 4F-MDMB-BUTINACA in Rats: A Forensic and Toxicological Perspective" Future Pharmacology 4, no. 4: 676-699. https://doi.org/10.3390/futurepharmacol4040036
APA StyleAbdelgadir, E. H., Al-Qudsi, J., Abu-Nukhaa, E. S., & Alsidrani, D. A. (2024). Subacute Toxicity and Pharmacokinetic Evaluation of the Synthetic Cannabinoid 4F-MDMB-BUTINACA in Rats: A Forensic and Toxicological Perspective. Future Pharmacology, 4(4), 676-699. https://doi.org/10.3390/futurepharmacol4040036