Pharmacokinetics of 11-nor-9-Carboxy-Δ9-Tetrahydrocannabinol (CTHC) After Intravenous Administration of CTHC in Healthy Human Subjects

Glaz-Sandberg, A; Dietz, Lisa; Nguyen, HoangKim; Oberwittler, Heike; Aderjan, R.; Mikus, Gerd

doi:10.1038/sj.clpt.6100199

Cited by 15 publications

(11 citation statements)

References 29 publications

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“…Plasma 11-OH-THC elimination half-life in 3 infrequent cannabis users was 19–24 h (14); THCCOOH elimination half-lives were 5.2 (0.08) and 6.2 (6.7) days in frequent and infrequent users, respectively (21). After 5-mg intravenous THCCOOH to 10 non–cannabis users, terminal serum THCCOOH elimination half-life was 17.6 (5.5) h; however, monitoring was for only 4 days, potentially underestimating this parameter (34). Considering our continuous THC dosing and long plasma metabolite excretion half-lives, 11-OH-THC and THCCOOH accumulation was expected.…”

Section: Discussionmentioning

confidence: 99%

Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous High-Dose Oral THC

Schwilke¹,

Schwope²,

Karschner³

et al. 2009

Clinical Chemistry

101

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BACKGROUND Δ9-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 THCCOOH 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) μg/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) μg/L, respectively, 22.5 h after the last dose. Escherichia coli β-glucuronidase hydrolysis of 264 cannabinoid specimens yielded statistically significant increases in THC, 11-OH-THC, and THCCOOH concentrations (P < 0.001), but conjugated concentrations were underestimated owing to incomplete enzymatic hydrolysis. CONCLUSIONS Plasma THC concentrations remained >1 μg/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 β-glucuronidase hydrolysis. These data will aid in the interpretation of plasma THC concentrations after multiple oral doses.

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Section: Discussionmentioning

confidence: 99%

Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous High-Dose Oral THC

Schwilke¹,

Schwope²,

Karschner³

et al. 2009

Clinical Chemistry

101

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“…Both 11-OH-THC and 11-nor-THC-COOH undergo glucuronidation by UGT1A9 and UGT1A10 (11-OH-THC) and UGT1A1 and UGT1A3 (11-nor-THC-COOH) (Mazur et al, 2009). As the 11-nor-THC-COOH, together with its acyl glucuronide conjugate, account for the majority (30–65%) of THC elimination (Glaz-Sandberg et al, 2007), altered CYP and UGT activity, as occurs during pregnancy, may significantly alter THC and metabolite exposures and pharmacology. Of note, the route of THC consumption will also alter the exposures to the metabolites.…”

Section: Pharmacokinetics Of Thc In Humansmentioning

confidence: 99%

“…By contrast following oral THC administration, 11-OH-THC plasma concentrations can exceed those of THC but decline with a shorter half-life (12 hrs) than THC suggesting that most of 11-OH-THC is formed during first pass in the liver (Grotenhermen, 2003; Wall et al, 1983). Because of the low clearance of 11-nor-THC-COOH (5.5 L/h), it is the main circulating compound following any route of THC administration (Glaz-Sandberg et al, 2007). Overall, these data show that the route of consumption of THC may result in distinctly different exposures and pharmacology.…”

Section: Pharmacokinetics Of Thc In Humansmentioning

confidence: 99%

Cannabis use during pregnancy: Pharmacokinetics and effects on child development

Grant

Petroff

Isoherranen

et al. 2018

Pharmacology & Therapeutics

192

159

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The broad-based legalization of cannabis use has created a strong need to understand its impact on human health and behavior. The risks that may be associated with cannabis use, particularly for sensitive subgroups such as pregnant women, are difficult to define because of a paucity of dose-response data and the recent increase in cannabis potency. Although there is a large body of evidence detailing the mode of action of Δ9‐tetrahydrocannabinol (THC) in adults, little work has focused on understanding how cannabis use during pregnancy may impact the development of the fetal nervous system and whether additional plant-derived cannabinoids might participate. This manuscript presents an overview of the historical and contemporary literature focused on the mode of action of THC in the developing brain, comparative pharmacokinetics in both pregnant and nonpregnant model systems and neurodevelopmental outcomes in exposed offspring. Despite growing public health significance, pharmacokinetic studies of THC have focused on nonpregnant adult subjects and there are few published reports on disposition parameters during pregnancy. Data from preclinical species show that THC readily crosses the placenta although fetal exposures appear lower than maternal exposures. The neurodevelopmental data in human and preclinical species suggest that prenatal exposure to THC may lead to subtle, persistent changes in targeted aspects of higher-level cognition and psychological well-being. There is an urgent need for well-controlled studies in humans and preclinical models on THC as a developmental neurotoxicant. Until more information is available, pregnant women should not assume that using cannabis during pregnancy is safe.

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“…-Tetrahydrocannabinol (THC) 3 and its 11-nor-9-carboxy-THC (THCCOOH) metabolite's urinary disposition are well characterized (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13), although less is known about frequent cannabis smoking and phase II cannabis metabolites. Recent research documented extended excretion of cannabinoids in abstinent chronic daily smokers' blood and urine given THC's lipophilicity and large body stores (8 -9, 14 -15 ).…”

mentioning

confidence: 99%

Urinary Cannabinoid Disposition in Occasional and Frequent Smokers: Is THC-Glucuronide in Sequential Urine Samples a Marker of Recent Use in Frequent Smokers?

et al. 2014

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BACKGROUND There is extended urinary excretion of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) in abstinent frequent cannabis smokers. We characterized THC, 11-OH-THC, THCCOOH, cannabidiol, cannabinol, THC-glucuronide, and THCCOOH-glucuronide disposition in urine of frequent and occasional cannabis smokers, and we propose a model to predict recent cannabis smoking. METHODS Frequent and occasional smokers resided on a closed research unit and smoked one 6.8% THC cannabis cigarette ad libitum. Urinary cannabinoids were quantified in each void by liquid chromatography-tandem mass spectrometry within 24 h of collection. RESULTS No urine samples had measureable THC, 11-OH-THC, cannabidiol, or cannabinol. THCCOOH, THC-glucuronide, and THCCOOH-glucuronide were measurable in all frequent smokers' urine and 60%, 100%, and 100% of occasional smokers' urine samples, respectively. Pre- and postdose maximal concentrations (non- and creatinine normalized) and probability of being positive were significantly higher in frequent smokers' samples. THC-glucuronide concentrations peaked 0.6–7.4 h after smoking; THCCOOH and THCCOOH-glucuronide concentrations were highly variable. At the newly adopted THCCOOH 175-μg/L World Anti-Doping Agency decision limit, only 50% of frequent smokers were positive 0–6 h postdose; no occasional smokers' samples were positive. An absolute %difference of ≥50% between 2 consecutive THC-glucuronide–positive samples with a creatinine-normalized concentration of ≥2 μg/g in the first sample predicted cannabis smoking with efficiencies of 93.1% in frequent and 76.9% in occasional smokers within 6 h of first sample collection. CONCLUSIONS These controlled urinary cannabinoid data provide a possible means of identifying recent cannabis intake in cannabis smokers' urine within a short collection time frame after smoking.

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Pharmacokinetics of 11-nor-9-Carboxy-Δ9-Tetrahydrocannabinol (CTHC) After Intravenous Administration of CTHC in Healthy Human Subjects

Cited by 15 publications

References 29 publications

Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous High-Dose Oral THC

Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous High-Dose Oral THC

Cannabis use during pregnancy: Pharmacokinetics and effects on child development

Urinary Cannabinoid Disposition in Occasional and Frequent Smokers: Is THC-Glucuronide in Sequential Urine Samples a Marker of Recent Use in Frequent Smokers?

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