Is adipose tissue suitable for detection of (synthetic) cannabinoids? A comparative study analyzing antemortem and postmortem specimens following pulmonary administration of JWH-210, RCS-4, as well as ∆9-tetrahydrocannabinol to pigs

Abstract

Examining fatal poisonings, chronic exposure may be reflected by the concentration in tissues known for long-term storage of drugs. Δ9-tetrahydrocannabinol (THC) persists in adipose tissue (AT), but sparse data on synthetic cannabinoids (SC) are available. Thus, a controlled pig study evaluating antemortem (AM) disposition and postmortem (PM) concentration changes of the SC 4-ethylnaphthalene-1-yl-(1-pentylindole-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indole-3-yl)methanone (RCS-4) as well as THC in AT was performed. The drugs were administered pulmonarily (200 µg/kg body weight) to twelve pigs. Subcutaneous (s.c.) AT specimens were collected after 15 and 30 min and then hourly up to 8 h. At the end, pigs were sacrificed and s.c., perirenal, and dorsal AT specimens were collected. The carcasses were stored at room temperature (RT; n = 6) or 4 °C (n = 6) and specimens were collected after 24, 48, and 72 h. After homogenization in acetonitrile and standard addition, LC–MS/MS was performed. Maximum concentrations were reached 0.5–2 h after administration amounting to 21 ± 13 ng/g (JWH-210), 24 ± 13 ng/g (RCS-4), and 22 ± 20 ng/g (THC) and stayed at a plateau level. Regarding the metabolites, very low concentrations of N-hydroxypentyl-RCS-4 (HO-RCS-4) were detected from 0.5 to 8 h. PM concentrations of parent compounds did not change significantly (p > 0.05) over time under both storage conditions. Concentrations of HO-RCS-4 significantly (p < 0.05) increased in perirenal AT during storage at RT. These results suggest a rapid distribution and persistence in s.c. AT. Furthermore, AT might be resistant to PM redistribution of parent compounds. However, significant PM increases of metabolite concentrations might be considered in perirenal AT.

A Systematic Study of the In Vitro Pharmacokinetics and Estimated Human In Vivo Clearance of Indole and Indazole-3-Carboxamide Synthetic Cannabinoid Receptor Agonists Detected on the Illicit Drug Market

“…Therefore, the presence of such compounds and their metabolites in body fluids after a considerable time is more likely to be evidence of tissue accumulation, subsequent leaching back into the circulatory system and metabolism of the unbound fraction. JWH- SCRAs have log P values which are similar to or greater than those of indole- and indazole-3-carboxamide SCRAs (and therefore likely similar or greater PPB), which may in part explain their extended detection windows in vivo [ 100 , 101 ], though specific structural features are likely also involved [ 39 ].…”

“…This unbound fraction will also be available for metabolism by hepatic and, potentially, extrahepatic enzymes. Whilst a great deal is known about the pharmacokinetics of naturally occurring cannabinoids such as Δ9-tetrahydrocannabinol (THC) [ 32 , 33 , 34 , 35 , 36 ] and its metabolites, less is known about the pharmacokinetics of the valinate and tert -leucinate indole and indazole-3-carboxamide SCRAs [ 37 , 38 , 39 ]. Like SCRAs, the most common routes of administration of THC are smoking and vaping.…”

“…Like SCRAs, the most common routes of administration of THC are smoking and vaping. THC is more bioavailable via inhalation compared to ingestion, and inhalation avoids first-pass metabolism leading to rapid onset of psychoactive effects [ 34 , 36 ]; is highly lipophilic (log P = 6.7 [ 39 ]) and has a low distribution into erythrocytes and a high plasma protein affinity (95–99% protein-bound in plasma) [ 33 ]. Synthetic cannabinoids are also lipophilic, with theoretical log P values in the literature ranging from 3.02–8.14 [ 18 , 19 , 20 , 21 ], although theoretical log P values reported for the valinate and tert -leucinate indole-/indazole-3-carboxamides indicate that they are amongst the least lipophilic of the SCRAs.…”

“…THC is distributed into the adipose tissue, especially in chronic users, with subsequent slow release from the adipose leading to long detection windows for THC and its metabolites [ 33 , 36 , 40 ]. Many SCRAs are also highly lipophilic; JWH-210 (4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone) (log P = 7.5) and RCS-4 (2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone) (log P = 5.6) have shown similar distribution to THC into the adipose tissue of experimentally exposed pigs [ 39 ], and long detection windows for other SCRAs in humans have also been reported [ 41 , 42 , 43 ]. However, lipophilicity is not the only determining factor for uptake by adipocytes [ 39 ], as some highly lipophilic drugs are not extensively distributed into adipose tissue [ 44 , 45 ] and structural features are also thought to contribute [ 46 , 47 ].…”

Detectability of cannabinoids in the serum samples of cannabis users: Indicators of recent cannabis use? A follow‐up study

“…4,5 However, delta-9-THC is distributed into tissues, such as adipose tissue. [6][7][8][9][10] After frequent cannabis consumption, delta-9-THC can accumulate in adipose tissue, in which it can be retained. 6,10 The subsequent release of delta-9-THC from adipose tissue (resulting in a long terminal half-life of delta-9-THC in blood 6 ) can complicate the interpretation of blood concentrations of delta-9-THC and its metabolites.…”