Disposition Kinetics of Cathinone and its Metabolites after Oral Administration in Rats.

BACKGROUND: Cathinone is a natural stimulant found in the Catha edulis plant. Its derivatives make up the largest group of new psychoactive substances. In order to better understand its effects, it is imperative to investigate its distribution, pharmacokinetics, and metabolic profile. However, the existing literature on cathinone remains limited. OBJECTIVE: This study aimed to investigate the disposition kinetics and metabolic profile of cathinone and its metabolite cathine through a single oral dose of cathinone administration in rats. METHODS: Cathinone and cathine concentrations were identified and quantified using ion trap liquid chromatography- mass spectrometry (LC-IT/MS). The metabolic profile in the serum, brain, lung, liver, kidney, and heart was analyzed at specific time points (0, 0.5, 2.5, 6, 12, 24, 48, and 72 hours) using the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method. RESULTS: The highest concentration of cathinone was found in the kidney (1438.6 µg/L, which gradually decreased to 1.97 within 48 h and disappeared after 72 h. Cathinone levels in the lungs, liver, and heart were 859, 798.9, and 385.8 µg/L, respectively, within half an hour. However, within 2.5 hours, these levels decreased to 608.1, 429.3, and 309.1 µg/L and became undetectable after 24 h. In the rat brain, cathinone levels dropped quickly and were undetectable within six hours, decreasing from 712.7 µg/L after 30 min. In the brain and serum, cathine reached its highest levels at 2.5 hours, while in other organs, it peaked at 0.5 hours, indicating slower conversion of cathinone to cathine in the brain and serum. CONCLUSION: This study revealed a dynamic interplay between cathinone disposition kinetics and its impact on organ-specific metabolic profiles in rats. These results have significant implications for drug development, pharmacovigilance, and clinical practices involving cathinone. Investigating the correlation between the changes in biomarkers found in the brain and the levels of cathinone and cathine is essential for informed decision- making in medical practices and further research into the pharmacological properties of cathinone.

Fatalities Involving Khat in Jazan, Saudi Arabia, 2018 to 2021.

Interpreting fatalities involving khat is challenging due to a lack of data on cathinone and cathine reference concentrations in postmortem tissues. This study investigated the autopsy findings and toxicological results of fatalities involving khat in Saudi Arabia's Jazan region from 1 January 2018 to 31 December 2021. All confirmed cathine and cathinone results in postmortem blood, urine, brain, liver, kidney, and stomach samples were recorded and analyzed. Autopsy findings and the manner and cause of death of the deceased were assessed. Saudi Arabia's Forensic Medicine Center investigated 651 fatality cases over four years. Thirty postmortem samples were positive for khat's active constituents, cathinone and cathine. The percentage of fatalities involving khat was 3% in 2018 and 2019 and increased from 4% in 2020 to 9% in 2021, when compared with all fatal cases. They were all males ranging in age from 23 to 45. Firearm injuries (10 cases), hanging (7 cases), road traffic accident (2 cases), head injury (2 cases), stab wounds (2 cases), poisoning (2 cases), unknown (2 cases), ischemic heart disease (1 case), brain tumor (1 case), and choking (1 case) were responsible for the deaths. In total, 57% of the postmortem samples tested positive for khat only, while 43% tested positive for khat with other drugs. Amphetamine is the drug most frequently involved. The average cathinone and cathine concentrations were 85 and 486 ng/mL in the blood, 69 and 682 ng/mL in the brain, 64 and 635 ng/mL in the liver, and 43 and 758 ng/mL in the kidneys, respectively. The 10th-90th percentiles of blood concentrations of cathinone and cathine were 18-218 ng/mL and 222-843 ng/mL, respectively. These findings show that 90% of fatalities involving khat had cathinone concentrations greater than 18 ng/mL and cathine concentrations greater than 222 ng/mL. According to the cause of death, homicide was the most common fatality involving khat alone (77%). More research is required, especially toxicological and autopsy findings, to determine the involvement of khat in crimes and fatalities. This study may help forensic scientists and toxicologists investigate fatalities involving khat.

Cathine and cathinone disposition kinetics and neurotransmitter profile in several organs of rats exposed to a single dose of Catha edulis (Vahl) Forssk. ex Endl. extract.

OBJECTIVES: Catha edulis (Vahl) Forssk. ex Endl. (Khat) is a stimulant plant that contains cathine and cathinone, which its abuses induce euphoria, alertness, and motor activity. Since the toxicokinetics of these substances remain unclear, this study was carried out to investigate the disposition kinetics of cathine and cathinone, the neurotransmitter profile, following a single dose of C. edulis extract in rats. METHODS: Twenty-four adult male Wistar albino rats (250-300 g) were randomly selected and divided into six groups of four rats each. All groups received a single oral dose of 2,000 mg/kg body weight, and blood and tissue samples from the brain, lung, heart, liver, and kidney were obtained at intervals of 0.5, 1, 2.5, 5, 12, and 24 h. The cathine and cathinone concentrations were identified and quantified using ion trap ultra-high performance liquid chromatography (HPLC-IT/MS). The neurotransmitter profile was detected using the quadrupole time of flight UPLC-QTOF/MS method. RESULTS: The lung, liver, and heart tissues attained the highest levels of cathine, while the highest level of cathinone was determined in the heart. Cathine and cathinone concentrations in the blood and heart peaked at 0.5 h. The concentrations peaked in the brain 2.5 h later, indicating that the heart had an immediate effect, whereas the brain had a longer-lasting one. They have longer half-lives (2.68 and 5.07 h, respectively) and may remain in the brain for longer durations (3.31 and 2.31 h, respectively). The neurotransmitters epinephrine, dopamine, norepinephrine, and serotonin were detected in a delayed, prolonged and organ-specific manner. CONCLUSIONS: Cathine and cathinone were deposited in considerable concentrations in all tissues analyzed, with the highest Cmax in the lung and Tmax in the heart tissues but not in the brain. In addition, neurotransmitters such as adrenaline, dopamine, norepinephrine, and serotonin were differentially detected in all tested samples in a organ-specific fashion. More study is needed to identify cathine and cathinone's effects on neurotransmitter profiles. Nevertheless, these findings provided a further basis for experimental, clinical, and forensic investigations.

Habitual khat chewing alters urinary inorganic profile in adult healthy males.

OBJECTIVES: Khat (Catha edulis) is a stimulant plant, and it is abusive to induce euphoria, alertness and activity. Concomitant use of medications and khat chewing predisposes to the appearance of drug interactions result in treatment failure or toxicity. This study determined the changes in the urinary inorganic profile in adult healthy males who are chewing khat compared with non-khat chewer males. METHODS: A total of 40 adult non-smoker healthy males (20 khat chewer and 20 non-khat chewer) aged 24-30 years were selected. Khat chewer samples were positive for cathinone and cathine and negative for other drug of abuse, while non-khat chewer samples were negative for drug of abuse include cathinone and cathine. Samples were selected according to their results in immunoassay and gas chromatography mass spectrometry (GCMS) analysis. Cathine and cathinone were confirmed using liquid chromatography mass spectrometry (LC-MSMS) analysis. Inorganic profile includes titanium (Ti), cobalt (Co), copper (Cu), zinc (Zn), cadmium (Cd), and lead (Pb) were determined by using inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: The levels of Ti, Co, Zn, Cd, and Pb in urine were significantly higher among the khat chewer group compared with non-khat chewer. Ti, Cd, Co, Pb and Zn urine levels were 0.5-, 1.5-, 1.15-, 5-, and 8.2-fold higher in the khat chewer group compared to non-khat chewer, respectively. CONCLUSIONS: We suggested that continuous khat chewing has a long term effect on metabolic pathway of therapeutic drugs that result in toxicity or failure of therapy.

Habitual khat chewing alters urinary inorganic profile in adult healthy males.

OBJECTIVES: Khat (Catha edulis) is a stimulant plant, and it is abusive to induce euphoria, alertness and activity. Concomitant use of medications and khat chewing predisposes to the appearance of drug interactions result in treatment failure or toxicity. This study determined the changes in the urinary inorganic profile in adult healthy males who are chewing khat compared with non-khat chewer males. METHODS: A total of 40 adult non-smoker healthy males (20 khat chewer and 20 non-khat chewer) aged 24-30 years were selected. Khat chewer samples were positive for cathinone and cathine and negative for other drug of abuse, while non-khat chewer samples were negative for drug of abuse include cathinone and cathine. Samples were selected according to their results in immunoassay and gas chromatography mass spectrometry (GCMS) analysis. Cathine and cathinone were confirmed using liquid chromatography mass spectrometry (LC-MSMS) analysis. Inorganic profile includes titanium (Ti), cobalt (Co), copper (Cu), zinc (Zn), cadmium (Cd), and lead (Pb) were determined by using inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: The levels of Ti, Co, Zn, Cd, and Pb in urine were significantly higher among the khat chewer group compared with non-khat chewer. Ti, Cd, Co, Pb and Zn urine levels were 0.5-, 1.5-, 1.15-, 5-, and 8.2-fold higher in the khat chewer group compared to non-khat chewer, respectively. CONCLUSIONS: We suggested that continuous khat chewing has a long term effect on metabolic pathway of therapeutic drugs that result in toxicity or failure of therapy.

Postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in rabbits over 24 h.

The interpretation of postmortem drug levels is complicated by changes in drug blood levels in the postmortem period, a phenomena known as postmortem drug redistribution. We investigated the postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in a rabbit model. Heroin (1 mg/kg) was injected into anesthetised rabbit; after 1 h, an auricular vein blood sample was taken and the rabbit was euthanised. Following death rabbits were placed in a supine position at room temperature and divided into three groups namely (1) immediate autopsy, (2) autopsy after 30 minutes and (3) autopsy 24 h after death. Various samples which included femoral blood, cardiac blood, lung, liver, kidney, vitreous humour, subcutaneous and abdominal fat, liver, bone marrow and skeletal muscle were taken. The samples were analysed with a validated LC-MS/MS method. It was observed that within minutes there was a significant increase in free morphine postmortem femoral blood concentration compared to the antemortem sample (0.01 ± 0.01 to 0.05 ± 0.02 mg/L).Various other changes in free morphine and metabolite concentrations were observed during the course of the experiment in various tissues. Principal component analysis was used to investigate possible correlations between free morphine in the various samples. Some correlations were observed but gave poor predictions (>20 % error) when back calculating. The results suggest that rabbits are a good model for further studies of postmortem redistribution but that further study and understanding of the phenomena is required before accurate predictions of the blood concentration at the time of death are possible.