Characterizing and Quantifying Extrahepatic Metabolism of (−)-Δ9-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, (±)-11-Hydroxy-Δ9-THC (11-OH-THC) (original) (raw)
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Forensic Science International, 2006
This study presents a new animal model, the Large White Pig, which was tested for studying cannabinoids metabolism. The first step has focused on determination of plasma kinetics after injection of D 9 -tetrahydrocannabinol (THC) at different dosages. Seven pigs received THC by intravenous injections (50, 100 or 200 mg/kg). Plasma samples were collected during 48 h. Determination of cannabinoids concentrations were performed by gas chromatography/mass spectrometry. Results showed that plasma kinetics were comparable to those reported in humans. Terminal half-life of elimination was 10.6 h and a volume of distribution of 32 l/kg was calculated. In a second step, this model was used to determine the kinetic profile of cannabinoids distribution in tissues. Eight Large White male pigs received an injection of THC (200 mg/kg). Two pigs were sacrificed 30 min after injection, two others after 2, 6 and 24 h. Different tissues were sampled: liver, kidney, heart, lung, spleen, muscle, fat, bile, blood, vitreous humor and several brain areas. The fastest THC elimination was noted in liver tissue, where it was completely eliminated in 6 h. THC concentrations decreased in brain tissue slower than in blood. The slowest THC elimination was observed for fat tissue, where the molecule was still present at significant concentrations 24 h later. After 30 min, THC concentration in different brain areas was highest in the cerebellum and lowest in the medulla oblongata. THC elimination kinetics noted in kidney, heart, spleen, muscle and lung were comparable with those observed in blood. 11-Hydroxy-THC was only found at high levels in liver. THC-COOH was less than 5 ng/g in most tissues, except in bile, where it increased for 24 h following THC injection. This study confirms, even after a unique administration, the prolonged retention of THC in brain and particularly in fat, which could be at the origin of different phenomena observed for heavy users such as prolonged detection of THC-COOH in urine or cannabis-related flashbacks. Moreover, these results support the interest for this animal model, which could be used in further studies of distribution of cannabinoids in tissues. #
Clinical Chemistry, 2009
BACKGROUND: ⌬ 9-Tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis and an active cannabinoid pharmacotherapy component. No plasma pharmacokinetic data after repeated oral THC administration are available. METHODS: Six adult male daily cannabis smokers resided on a closed clinical research unit. Oral THC capsules (20 mg) were administered every 4-8 h in escalating total daily doses (40-120 mg) for 7 days. Free and glucuronidated plasma THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THC COOH) were quantified by 2-dimensional GC-MS during and after dosing. RESULTS: Free plasma THC, 11-OH-THC, and THC-COOH concentrations 19.5 h after admission (before controlled oral THC dosing) were mean 4.3 (SE 1.1), 1.3 (0.5), and 34.0 (8.4) g/L, respectively. During oral dosing, free 11-OH-THC and THCCOOH increased steadily, whereas THC did not. Mean peak plasma free THC, 11-OH-THC, and THCCOOH concentrations were 3.8 (0.5), 3.0 (0.7), and 196.9 (39.9) g/L, respectively, 22.5 h after the last dose. Escherichia coli -glucuronidase hydrolysis of 264 cannabinoid specimens yielded statistically significant increases in THC, 11-OH-THC, and THCCOOH concentrations (P Ͻ 0.001), but conjugated concentrations were underestimated owing to incomplete enzymatic hydrolysis. CONCLUSIONS: Plasma THC concentrations remained Ͼ1 g/L for at least 1 day after daily cannabis smoking and also after cessation of multiple oral THC doses. We report for the first time free plasma THC concentrations after multiple high-dose oral THC throughout the day and night, and after Escherichia coli -glucuronidase hydrolysis. These data will aid in the interpretation of plasma THC concentrations after multiple oral doses.
British Journal of Clinical Pharmacology, 2020
Population pharmacokinetic models of Δ9-tetrahydrocannabinol (THC) have been developed for THC plasma and blood concentration data. Often, only the metabolites of THC are measurable when blood samples are obtained. Therefore, we performed a population pharmacokinetic analysis of THC, 11-OH-THC and THCCOOH plasma concentration data from a Phase I clinical trial of THC smoking. Methods: Frequently obtained plasma THC, 11-OH-THC and THCCOOH concentration data were obtained over 168 h from 6 subjects who smoked low (15.8 mg) and high dose (33.8 mg) THC cigarettes on 2 occasions. Bayesian estimates of the THC pharmacokinetic model from each individual for each dose were fixed prior to the sequential pharmacokinetic analysis of the metabolites. Results: A 3-compartment model of THC was developed that has a steady-state volume of distribution (Vd SS) of 3401 ± 788 L and a clearance of 0.72 ± 0.10 L/min. 11-OH-THC was characterized by 50 ± 6% of the THC being directly cleared to a 3-compartment model with a Vd SS of 415.2 ± 4.3 L and clearance of 0.78 ± 0.05 L/min. The THCCOOH model shared the central compartment of the 11-OH-THC model with a Vd SS of 29.1 ± 0.05 L and a clearance of 0.12 ± 0.02 L/min. First order kinetics were observed for THC and THCCOOH between the low and high doses, but a nonlinear pattern was observed for 11-OH-THC. Conclusion: We describe the pharmacokinetics of THC, 11-OH-THC and THCCOOH including inter-and intraindividual variability of the parameter estimates of the model.
International Journal of Molecular Sciences, 2021
The rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to Δ9-tetrahydrocannabinol (Δ9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that Δ9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg Δ9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to Δ9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, Δ9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACCα, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expr...
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Iranian journal of psychiatry, 2012
Cannabis is one of the most widely abused substances throughout the world. The primary psychoactive constituent of cannabis, delta 9-tetrahydrocannabinol (▵(9_)THC), produces a myriad of pharmacological effects in animals and humans. Although it is used as a recreational drug, it can potentially lead to dependence and behavioral disturbances and its heavy use may increase the risk for psychotic disorders.Many studies that endeavor to understand the mechanism of action of cannabis concentrate on pharmacokinetics and pharmacodynamics of cannabinoids in humans. However, there is limited research on the chronic adverse effects and retention of cannabinoids in human subjects.Cannabis can be detected in body fluids following exposure through active/passive inhalation and exposure through breastfeeding. Cannabis detection is directly dependent on accurate analytical procedures for detection of metabolites and verification of recent use.In this review, an attempt has been made to summarize ...
In vitro and in vivo human metabolism of the synthetic cannabinoid AB-CHMINACA
Drug testing and analysis, 2015
N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide (AB-CHMINACA) is a recently introduced synthetic cannabinoid. At present, no information is available about in vitro or in vivo human metabolism of AB-CHMINACA. Therefore, biomonitoring studies to screen AB-CHMINACA consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated the in vitro metabolism of AB-CHMINACA using human liver microsomes (HLMs). Formation of AB-CHMINACA metabolites was monitored using liquid chromatography coupled to time-of-flight mass spectrometry. Twenty-six metabolites of AB-CHMINACA were detected including seven mono-hydroxylated and six di-hydroxylated metabolites and a metabolite resulting from N-dealkylation of AB-CHMINACA, all produced by cytochrome P450 (CYP) enzymes. Two carboxylated metabolites, likely produced by amidase enzymes, and five glucuronidated metabolites were also formed. Five mono-...
Journal of Mass Spectrometry, 2009
In Cannabis sativa, 9-Tetrahydrocannabinolic acid-A ( 9-THCA-A) is the non-psychoactive precursor of 9-tetrahydrocannabinol ( 9-THC). In fresh plant material, about 90% of the total 9-THC is available as 9-THCA-A. When heated (smoked or baked), 9-THCA-A is only partially converted to 9-THC and therefore, 9-THCA-A can be detected in serum and urine of cannabis consumers. The aim of the presented study was to identify the metabolites of 9-THCA-A and to examine particularly whether oral intake of 9-THCA-A leads to in vivo formation of 9-THC in a rat model. After oral application of pure 9-THCA-A to rats (15 mg/kg body mass), urine samples were collected and metabolites were isolated and identified by liquid chromatography-mass spectrometry (
Comparative Pharmacokinetics of Δ9-Tetrahydrocannabinol in Adolescent and Adult Male Mice
Journal of Pharmacology and Experimental Therapeutics, 2020
We investigated the pharmacokinetic properties of D 9-tetrahydrocannabinol (D 9-THC), the main psychoactive constituent of cannabis, in adolescent and adult male mice. The drug was administered at logarithmically ascending doses (0.5, 1.6, and 5 mg/kg, i.p.) to pubertal adolescent (37-day-old) and adult (70day-old) mice. D 9-THC and its first-pass metabolites-11hydroxy-D 9-THC and 11-nor-9-carboxy-D 9-THC (11-COOH-THC)-were quantified in plasma, brain, and white adipose tissue (WAT) using a validated isotope-dilution liquid chromatography/tandem mass spectrometry assay. D 9-THC (5 mg/kg) reached 50% higher circulating concentration in adolescent mice than in adult mice. A similar age-dependent difference was observed in WAT. Conversely, 40%-60% lower brain concentrations and brain-to-plasma ratios for D 9-THC and 50%-70% higher brain concentrations for D 9-THC metabolites were measured in adolescent animals relative to adult animals. Liver microsomes from adolescent mice converted D 9-THC into 11-COOH-THC twice as fast as adult microsomes. Moreover, the brains of adolescent mice contained higher mRNA levels of the multidrug transporter breast cancer resistance protein, which may extrude D 9-THC from the brain, and higher mRNA levels of claudin-5, a protein that contributes to blood-brain barrier integrity. Finally, administration of D 9-THC (5 mg/kg) reduced spontaneous locomotor activity in adult, but not adolescent, animals. The results reveal the existence of multiple differences in the distribution and metabolism of D 9-THC between adolescent and adult male mice, which might influence the pharmacological response to the drug. SIGNIFICANCE STATEMENT Animal studies suggest that adolescent exposure to D 9-tetrahydrocannabinol (D 9-THC), the intoxicating constituent of cannabis, causes persistent changes in brain function. These studies generally overlook the impact that age-dependent changes in the distribution and metabolism of the drug might exert on its pharmacological effects. This report provides a comparative analysis of the pharmacokinetic properties of D 9-THC in adolescent and adult male mice and outlines multiple functionally significant dissimilarities in the distribution and metabolism of D 9-THC between these two age groups.