Abstract
BACKGROUND:
This research focused on establishing a highly sensitive and reliable gas chromatography–mass spectrometry (GC-MS) method for detecting and quantifying 5F-MDMB-PICA in rat plasma, as well as thoroughly assessing its pharmacokinetic characteristics, such as plasma half-life and volume of distribution.
MATERIAL AND METHODS:
Male Wistar rats were orally administered 5F-MDMB-PICA at two concentrations: 5 mg/kg and 50 mg/kg body weight. Following administration, blood samples were collected for pharmacokinetic analysis. To optimize analyte recovery and minimize matrix effects, plasma samples were subjected to a dual extraction protocol combining liquid–liquid extraction and protein precipitation. The processed samples were subsequently analyzed using GC-electron ionization/MS.
RESULTS:
The analytical method was validated in accordance with Food and Drug Administration guidelines, demonstrating excellent selectivity and robust calibration curves over a concentration range of 0.5–1000 ng/mL, exhibiting linearity with a correlation coefficient (R2) of 0.99. The limit of quantitation (LOQ) was established at 10 ng/mL. Interassay precision, expressed as relative standard deviation (RSD%), ranged from 2.54% to 3.94%, while interassay accuracy (bias%) was maintained at 9.44% for the analyte. Subsequently, the validated method was successfully applied to pharmacokinetic profiling of 5F-MDMB-PICA in rat plasma. Following oral administration, 5F-MDMB-PICA was rapidly absorbed, with a plasma half-life (t1/2) spanning 14.82–26.16 h. The volume of distribution (Vd) ranged from 86.43 to 205.39 L, and plasma clearance rates were measured between 2.28 and 9.60 L/h.
CONCLUSIONS:
A precise and accurate GC-MS method was successfully developed and validated for the quantification of 5F-MDMB-PICA in rat plasma, enabling comprehensive assessment of its pharmacokinetics, bioavailability, and tissue distribution. These results provide valuable insights that may enhance the understanding of the pharmacokinetic and pharmacodynamic profiles of 5F-MDMB-PICA.
Keywords: 5F-MDMB-PICA, Granisetron, half-life, synthetic cannabinoid, volume of distribution
Introduction
Synthetic cannabinoids (SCs) are a class of designer drugs that mimic the effects of naturally occurring cannabinoids found in the Cannabis sativa plant, primarily Δ9-tetrahydrocannabinol (Δ9-THC).[1,2] Developed initially for research purposes, SCs have gained popularity as recreational substances due to their potent psychoactive effects and accessibility through illicit markets. However, their structural diversity, high receptor affinity, and unpredictable pharmacological profiles have raised significant public health concerns. Many SCs exhibit stronger and more adverse effects than natural cannabinoids, often leading to severe toxicity, dependence, and fatal intoxications.[3] Due to these risks, numerous SCs have been subjected to legal control globally, although new analogs continue to emerge, challenging regulatory efforts.
5F-MDMB-PICA, chemically identified as methyl (2S)-2-{[1-(5-fluoropentyl)-1H-indole-3-carbonyl] amino}-3,3-dimethylbutanoate, was first reported in 2016.[4] Bannister et al. were the initial researchers to synthesize and characterize this compound, employing it to explore the pharmacological properties of SCs bearing valinate or tert-leucinate structural motifs.[5] Since April 2019, 5F-MDMB-PICA has been listed as a controlled substance in Schedule I.[6] It demonstrates high binding affinity and potent agonist activity at both cannabinoid receptor type 1 (CB1) and type 2 (CB2), activating these receptors at low nanomolar concentrations, indicative of strong receptor engagement. Compared to Δ9-THC, 5F-MDMB-PICA acts as a significantly more efficacious full agonist at both CB1 and CB2 receptors.[7] Furthermore, Noble et al. identified 5F-MDMB-PICA as the most pharmacologically active indole-3-carboxamide derivative, exhibiting CB1 and CB2 receptor activities approximately threefold greater than those of JWH-018.[8]
The most frequently observed physical side effects of 5F-MDMB-PICA include motor imbalances and visual disturbances such as reddened conjunctivae, ptosis (droopy eyelids), and mydriasis (dilated pupils). In addition, notable mental and behavioral effects consist of mood instability, aggressive and unpredictable behavior, confusion, altered time perception, increased talkativeness, and impaired or slurred speech.[4] The metabolism of 5F-MDMB-PICA is predicted to produce metabolites comparable to those seen in structurally related SCs. After hydrolysis of 5F-terminal ADBICA’s amide activity, hydrolysis of the methyl ester yields many metabolites. Similar findings were made for a number of additional synthetic cannabinoids with a “valine or tert-leucine” moiety. Many SCs, including 5F-ABICA, can undergo hydrolysis of their secondary amide bond, leading to the formation of a common metabolite: 1-(5-fluoropentyl)-1H-indole-3-carboxylic acid. Compounds such as 5F-ADBICA (N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide), 5F-PB-22 or MMB-2201 (methyl N-[1-(5-fluoropentyl)-1H-indole-3-yl] carbonyl valinate), and 5F-PB-22 or MMB-22 follow similar metabolic pathways. In addition, hydrolytic defluorination can result in the formation of MDMB-PICA, the nonfluorinated analog of 5F-MDMB-PICA, which shares a similar metabolic profile. This transformation has been observed in other structurally related SC pairs.[9]
Previous research employing unique drug detection methodologies reported the identification of the SC, 5F-MDMB-PICA, in postmortem blood samples analyzed by LC-MS/MS in Germany in 2020. Subsequently, in 2021, Krotulski et al. developed and validated an LC-MS/MS analytical method for detecting 5F-MDMB-PICA in rat plasma, utilizing liquid-liquid extraction for sample preparation.[10]
Despite the growing interest in this SC, data on its pharmacokinetic characteristics – particularly its half-life and volume of distribution (Vd) – remain scarce. To address this gap, the present work aims to develop a sensitive and reliable gas chromatography–mass spectrometry (GC-MS) method for the detection and quantification of 5F-MDMB-PICA in rat plasma and to investigate its pharmacokinetic profile, including half-life, Vd, and plasma clearance.
Materials and Methods
Chemicals
Certified reference standards of 5F-MDMB-PICA (purity ≥98%) were obtained from Cayman Chemicals Ltd. (Ann Arbor, MI, USA). HPLC-grade methanol (≥99.9%) was purchased from CIMAT (Riyadh, Saudi Arabia). Acetonitrile, acetic acid (≥99.8%), 1-chlorobutane (≥99%), ammonium hydroxide solution (28%–30%), and formic acid (UHPLC grade) were sourced from Sigma-Aldrich (Germany). Solid-phase extraction (SPE) cartridges (C18, 200 mg/3 mL) were procured from United Chemical Technologies, Inc. (USA). Ethyl acetate (≥99%, HPLC grade) was supplied by ChemLab, while dichloromethane (DCM) and isopropanol (≥99.8%) were provided by Riedel-de Haën. Potassium dihydrogen phosphate was obtained from Loba Chemie (India).
Instruments and instrumental parameters
The analytical setup consisted of an Agilent 7890B GC with Agilent 5977B MS and the Autosampler. Chromatographic separation was achieved using an Agilent HP-5MS GC column (5%-phenyl)-methyl polysiloxane, measuring 30 m × 250 µm with a 0.25 µm film thickness. Helium gas (>99.999% purity) was employed as the carrier gas at a constant flow rate of 1 mL/min. Samples of 1 µL volume were introduced in splitless injection mode, with both the injector and transfer line temperatures maintained at 280°C. Electron impact ionization was conducted at 70 eV. Both qualitative and quantitative analyses were carried out in selected ion monitoring (SIM) mode, targeting ions with m/z values of 110, 136, 144, 159, 232, 312, 320, and 376.
Methodological techniques and scientific methods
Analytical methods
Rat plasma samples, calibration standards, and quality control (QC) specimens were systematically prepared for quantitative evaluation. Calibration curves were constructed using eight nonzero standards, with concentrations ranging from 0.5 to 1000 ng/mL, derived from serial dilutions of 5F-MDMB-PICA standard substock solutions. QC samples were formulated at low, medium, and high concentrations of 15, 75, and 300 ng/mL, respectively. Each preparation involved a plasma matrix volume of 0.5 mL. An internal standard (IS), at a fixed concentration of 50 µg/mL, was consistently incorporated into all calibration, QC, and plasma samples to ensure analytical accuracy and precision.
Liquid–liquid extraction procedures
First extraction method
In 5-mL tubes, 0.5 mL rat plasma was mixed with 50 µL IS (50 µg/mL), 1.5 mL acetonitrile, 0.5 mL 10 M ammonium formate, and 0.5 mL phosphate buffer. After vortexing for 3 min and centrifugation at 3000 rpm for 5 min, the supernatant was evaporated under nitrogen. The residue was reconstituted in 50 µL ethyl acetate and transferred to an autosampler vial for GC-MS analysis.
Second extraction method
To 0.5 mL of plasma spiked with 1 µg/mL 5F-MDMB-PICA in 5-mL polypropylene tubes, 50 µL of IS (50 µg/mL) and 1 mL acetonitrile were added. After vortexing for 3 min, samples were centrifuged at 3000 rpm for 5 min. The supernatant was transferred to a clean tube and evaporated under nitrogen to about 1 mL. Then, 0.5 mL of 1 M potassium bicarbonate and 3 mL ethyl acetate were added, followed by vortexing for 3 min and centrifugation at 3000 rpm for 5 min for phase separation. The organic layer was collected, evaporated to dryness under nitrogen, and reconstituted in 50 µL ethyl acetate before GC-MS analysis.
Third extraction method
In 5-mL polypropylene tubes, 0.5 mL plasma samples were spiked with 50 µL IS (50 µg/mL) and vortexed for 3 min. After centrifugation at 3000 rpm for 5 min, the supernatant was transferred to a new tube and evaporated under nitrogen to 0.5 mL. Subsequently, 1 mL distilled water and 3 mL 1-chlorobutane were added, followed by vortexing for 3 min and centrifugation at 3000 rpm for 5 min to separate phases. The organic layer was collected into a glass tube, evaporated to dryness under nitrogen, and reconstituted in 100 µL ethyl acetate. The final extract was transferred to an autosampler vial with a glass insert for GC-MS analysis.
Method validation
The analytical method was validated following ASB Standard 036 guidelines,[11,12] evaluating key parameters such as calibration linearity, precision, accuracy, limit of detection (LOD), and limit of quantification (LOQ).
Drug preparation and animals
5F-MDMB-PICA was initially dissolved in dimethyl sulfoxide (DMSO) to achieve a final DMSO concentration of 5% (v/v) and subsequently diluted with corn oil to obtain the required dosing volume. The same mixture of DMSO and corn oil was used as the vehicle control in all experiments.
Eighteen male Wistar rats, aged 12 weeks and weighing 150–160 g, were procured from the Animal Care Centre at King Saud University, Riyadh, Saudi Arabia.
The animals were maintained in polypropylene cages housing six rats each, under a controlled 12-h light/dark cycle, at a regulated temperature of 23°C ± 2°C and relative humidity of 50%–60%. They had unrestricted access to food and water throughout the study. All experimental protocols adhered to the ethical standards established by the Standing Committee for Scientific Research Ethics at Naif Arab University for Security Sciences and complied with international guidelines for laboratory animal care and use.
A 1-week acclimatization period was implemented before initiating the experimental procedures.
Experimental design
The single-dose study was conducted in accordance with OECD guideline 423 for chemical testing.[13] Eighteen male rats were randomly assigned to three groups, including one control group. For the acute toxicity assessment, two treatment groups (n = 6 each) received oral gavage doses of 5F-MDMB-PICA at 5 mg/kg and 50 mg/kg body weight, respectively. These dose levels were selected based on reported typical usage patterns among drug users, with synthetic cannabinoid doses ranging from 0.5 to 20 mg depending on the route of administration.[14] Moreover, similar dosing regimens have been employed in previous studies investigating novel psychoactive substances.[15]
Doses are administered in an orderly manner, and the resulting effects and signs of abuse are monitored around the clock. Toxic pharmacokinetics primarily aims, through studies of kinetic toxicity models, to confirm that experimental animals received the specified dose. Toxicity is then evaluated based on the symptoms and behaviors observed following the administration of toxic drug doses, as well as the timing and progression of the toxic effects. The dosage levels used in toxicokinetics are usually higher than those used in pharmacokinetics, which in turn can lead to changes in the same kinetic factors such as dissolution, absorption, distribution, protein binding, and metabolism. Furthermore, the dose causes significant changes in the design and interpretation of studies.
Six animals in a control group were given only vehicle control (DMSO: total concentration was 5% with corn oil added to the final volume).
Using indwelling catheters, 400 µL blood samples were collected from each rat at baseline (5 min predose) and at 30, 60, 90, 120, and 240 min following a single oral administration of 5F-MDMB-PICA (5 mg/kg). Sampling was performed with 1 mL tuberculin syringes, and blood was immediately transferred into 1.5 mL tubes containing 5 µL of 1000 IU/mL K3-EDTA (Thomas Scientific) as an anticoagulant and preservative. Samples were stored at −20°C until analysis.
Method accuracy was determined by analyzing 5F-MDMB-PICA at three QC concentrations – low (LQC), medium (MQC), and high (HQC) – each in triplicate. Precision was evaluated by calculating the relative standard deviation (RSD) of repeated QC measurements, with an acceptance threshold of RSD ≤ 15%. Accuracy was expressed as the percentage bias relative to nominal concentrations.
Pharmacokinetic calculations[16]
Noncompartmental analysis was used to calculate the pharmacokinetic parameters (WinNonlin Phoenix 6.0; Pharsight, Mountain View, CA, USA).
The initial concentration (C0) was calculated using the equation:
C0 = ln(γ−intercept)
where:
C0 is the initial concentration (concentration at time zero)
ln denotes the natural logarithm.
The apparent Vd was determined using the following equation:
where:
Vd is the apparent Vd
D is the administered dose
Cp is the plasma concentration.
The elimination rate (K) was calculated as:
K = Slope × (–κe)
where:
κe is the natural log conversion factor (−2.303).
The terminal phase half-life (t1/2) was calculated using the formula:
where:
K: The elimination rate.
The apparent total clearance after per oral dosage (CL) was calculated as:
CL = K ×Vd
Where:
Vd: volume of distribution
K: elimination rate.
Statistical analysis
Noncompartmental pharmacokinetic analysis was conducted using Microsoft Excel. Key pharmacokinetic parameters – including half-life (t1/2), standard deviation, RSD, and accuracy (bias%) – were calculated for each concentration–time profile. Descriptive statistics were used to evaluate interindividual variability and overall method performance.[16]
Results and Discussion
Method validation
Selected ion monitoring mode
The mass spectrometer was operated in selected ion monitoring (SIM) mode using electron ionization to specifically detect the target analyte, 5F-MDMB-PICA, along with the IS, Granisetron. Figure 1 represents SIM mass spectrums of 5F-MDMB-PICA and IS (Granisetron). Ions monitored were m/z 232, 376, and 330 for the analyte and m/z 159, 136, and 312 for IS.
Figure 1.
Mass spectrum for analyte 5F-MDMB-PICA and internal standard (Granisetron)
Linearity
Calibration curves for 5F-MDMB-PICA were constructed using standard concentrations of 0.5, 2, 5, 10, 20, 50, 100, 500, and 1000 ng/mL. Linearity was assessed by calculating the correlation coefficient (R²) of the regression line, which was found to be 0.99 – well within the acceptable range for quantitative bioanalytical methods. A strong linear relationship was observed between the peak area ratio of 5F-MDMB-PICA to the IS and the corresponding spiked blood concentrations within the 0.5–1000 ng/mL range [Figure 2].
Figure 2.
Peak area response (5F-MDMB-PICA/IS)
Accuracy and precision
The analytical method was validated for precision and accuracy at three quality control (QC) concentrations: low (LQC, 15 ng/mL), medium (MQC, 75 ng/mL), and high (HQC, 300 ng/mL). Each level was analyzed in triplicate (n = 6). Precision was expressed as the RSD%, and accuracy as the percentage bias from the nominal concentration. Both precision and accuracy met the acceptance criteria of ≤15%, in accordance with regulatory guidelines.[17] Interassay precision and accuracy for 5F-MDMB-PICA at the three QC levels are presented in Tables 1 and 2. The validated method exhibited excellent reliability for the quantitative analysis of 5F-MDMB-PICA in rat plasma.
Table 1.
Precision (recovery %) and accuracy (bias %) of 5F-MDMB-PICA quantification
| Replicate | Concentration (ng/mL) | Recovered concentration (ng/mL) | Bias (%) ±15% | Recovery (%) (85%–115%) |
|---|---|---|---|---|
| R1 | 15 | 15.9 | 6.00 | 106 |
| R2 | 15 | 16.5 | 10.00 | 110 |
| R3 | 15 | 17.2 | 14.67 | 114.67 |
| R1 | 75 | 81.5 | 8.67 | 108.67 |
| R2 | 75 | 83.6 | 11.47 | 111.47 |
| R3 | 75 | 86.2 | 14.93 | 114.93 |
| R1 | 300 | 325.5 | 8.50 | 108.5 |
| R2 | 300 | 322.2 | 7.40 | 107.4 |
| R3 | 300 | 310.1 | 3.37 | 103.37 |
| Mean | 9.44 | 109.44 | ||
Table 2.
Statistics data for 5F-MDMB-PICA interassay precision (relative standard deviation %)
| Interassay (n=3) | |||
|---|---|---|---|
| Plasma concentration (ng/mL) | Mean recovery concentration (ng/mL) | SD | RSD% (<15%) |
| 15 | 16.53 | 0.65 | 3.94 |
| 75 | 83.77 | 2.35 | 2.81 |
| 300 | 319.27 | 8.11 | 2.54 |
RSD: Relative standard deviation, SD: Standard deviation
Analytical processes that have been validated worked well in the quantitative determination of 5F-MDMB-PICA in rat plasma samples. Eighteen rats were included in the study. Six rats received an oral gavage of 5F-MDMB-PICA at a single dose of 5 mg/kg, defined as Group I, while another six rats received an oral gavage of 5F-MDMB-PICA at a higher dose of 50 mg/kg, defined as Group II. The means of drug recovery results from rat plasma according to the duration of the first dosage regarding Group I were 30 min (0.5 h) = 32.96, 60 min (1 h) = 56.34, 90 min (1.5 h) = 55.56, 120 min (2 h) = 54.88, 240 min (4 h) = 52.13. Moreover, regarding Group II, 30 min (0.5 h) = 29.36, 60 min (1 h) = 232.10, 90 min (1.5 h) = 227.01, 120 min (2 h) = 221.99, and 240 min (4 h) = 201.85 [Table 3].
Table 3.
Temporal profile of 5F-MDMB-PICA concentrations in rat plasma postadministration
| Time (h) | 0.5 | 1 | 1.5 | 2 | 4 |
|---|---|---|---|---|---|
| Plasma concentration means for dose 5 mg/kg | 32.96 | 56.34 | 55.56 | 54.88 | 52.13 |
| Log for dose 5 mg/kg | 1.51 | 1.75 | 1.74 | 1.73 | 1.71 |
| Plasma concentration means for dose 50 mg/kg | 29.36 | 232.10 | 227.01 | 221.99 | 201.85 |
| Log for dose 50 mg/kg | 1.46 | 2.36 | 2.35 | 2.34 | 2.30 |
A linear correlation was observed between the time postadministration and plasma concentrations of 5F-MDMB-PICA following oral gavage at both 5 mg/kg and 50 mg/kg doses in rats, indicating time-dependent systemic exposure [Figure 3].
Figure 3.
Linear correlation between time postadministration and plasma concentration of 5F-MDMB-PICA in rats following oral gavage at doses of 5 mg/kg and 50 mg/kg
There was no interference at the retention times of 5F-MDMB-PICA, and IS was observed, indicating that the analyzed method was acceptable. With a total run time of 12 min, the retention time (RT) for 5F-MDMB-PICA and IS was 8.82 and 9.45 min, respectively.
The half-life (t1/2) of 5F-MDMB-PICA at a dosage of 5 mg/kg in Group I was 26.16 h, while Vd was 86.43 ml and plasma clearance (CL) was 2.28 L/h. On the other hand, a 5F-MDMBPICA dosage of 50 mg/kg (Group II) had a lower plasma half-life (t1/2 = 14.82 h) than Group I. According to Vd (205.39 ml), it is comparatively higher. Furthermore, the plasma clearance increased to 9.60 L/h. During 2019 and 2020, 5F-MDMB-PICA was the most regularly seen synthetic cannabis molecule in the United States, and the drug is still prevalent today. Although its extensive use and popularity, little attention has been paid to the effect of 5F-MDMB-PICA in animal experiments.[18] This study presents the pharmacokinetic results of 5F-MDMB-PICA in plasma half-life (t1/2) within the range of 14.82 to 26.16 h and volume distribution (Vd) in the range of 86.43 to 205.39 L. In addition, plasma clearance (CL) ranged from 2.28 to 9.60 L/h. At least for the doses examined, this is consistent with simple linear kinetics.
The results demonstrated that 5F-MDMB-PICA exhibits a terminal half-life (t1/2) ranging from 14.82 to 26.16 h following oral administration in rats. This elimination rate is substantially slower than that of other SCs. For comparison, previous studies have reported t1/2 values of approximately 5–6 hours for AM2201 in rats,[19] and between 7 and 12 hours for CUMYL-PICA and 5F-CUMYL-PICA when administered intraperitoneally.[20] The extended half-life observed for 5F-MDMB-PICA may have clinical relevance, potentially increasing the risk of cumulative toxicity and prolonged adverse effects.
The pharmacokinetic profile of 5F-MDMB-PICA suggests that the route of administration significantly influences its half-life and systemic exposure. Therefore, further studies comparing inhalation, injection, and oral routes are warranted to understand the impact on its absorption and elimination kinetics.
Notably, a dose-dependent reduction in t1/2 was observed, with higher doses exhibiting faster clearance. This trend suggests the presence of nonlinear pharmacokinetics at elevated concentrations, potentially due to saturation of metabolic or excretory pathways. Given the high potency and efficacy of 5F-MDMB-PICA, these properties raise important concerns regarding its safety in human use, especially considering its association with severe intoxication events and toxicological outcomes.
While the full spectrum of effects observed in animal models may not directly translate to humans, clinical reports indicate that synthetic cannabinoids can induce serious adverse events, including prolonged hypothermia in some users.[21] Therefore, understanding the pharmacokinetic behavior of 5F-MDMB-PICA is critical for risk assessment and regulatory control.
Conclusion
A sensitive and accurate GC-MS method was successfully developed and validated for quantifying 5F-MDMB-PICA in rat plasma, enabling comprehensive evaluation of its pharmacokinetics, bioavailability, and tissue distribution. Following oral administration, 5F-MDMB-PICA was rapidly absorbed, with a plasma half-life (t1/2) ranging from 14.82 to 26.16 h, Vd between 86.43 and 205.39 L, and plasma clearance (CL) varying from 2.28 to 9.60 L/h. These findings provide critical insights into the pharmacokinetic and pharmacodynamic profiles of 5F-MDMB-PICA, offering valuable data to support further physiological and toxicological investigations of this compound.
The relatively large Vd indicates extensive tissue uptake, which may contribute to the prolonged duration of its effects. In addition, the moderate clearance rate suggests that the compound is eliminated at a pace consistent with sustained biological activity. This study lays important groundwork for future research aimed at understanding the risks associated with 5F-MDMB-PICA use, as well as improving detection methods in forensic and clinical contexts. Continued investigation into its metabolism and toxicity is essential for developing effective regulatory policies and treatment strategies.
Ethical approval
Ethical approval for animal use was granted by the Institutional Ethical Committee for Animal Laboratory Experiments (Approval No. Nauss-Rec-22-02), with all procedures conducted in compliance with NIH guidelines for experimental animal care.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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