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.
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.
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DOI：
10.3390/molecules26051396
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发表时间：
2021-03-05
期刊：
影响因子：
--
通讯作者：
McKenzie C
中科院分区：
文献类型：
--
作者：
Brandon AM;Antonides LH;Riley J;Epemolu O;McKeown DA;Read KD;McKenzie C
采用体外药代动力学研究方法，对市场上发现的12种非法大麻受体激动剂的对映体进行了研究，考察了它们的理化参数和构效关系。实验得到的对数D7.4从2.81(AB-FUBINACA)到4.95(MDMB-4EN-PINACA)，所有被测试的SCRA都是高蛋白结合的，从88.9±0.49%((R)-4F-MDMB-BINACA)到99.5±0.08%((S)-MDMB-FUBINACA)。大多数被测试的SCRA在体外能在混合的人肝微体(PHLM)和混合的冷冻保存的人肝细胞(PHHPEs)中被迅速清除。在PHLM110±34.5((S)-AB-FUBINACA)至3216±607mLmin−1 kg−1((S)-AMB-FUBINACA)。在pH值为0.34±0.0 9(S)-AB-FUBINACA和1.39±0.2 7(S)-−-5F-−-PINACA条件下，−1 kg−1((S)-5F-AMB-PINACA)为17.79±0.2 0m L；呋喃甲酸酯、叔亮氨酸、吲哚和吲哚-3-甲酰胺的SCRA在体外通常代谢迅速，但在体内却高度结合蛋白质，因此在体内预测CLH的速度要比Clint慢得多。这可能会导致尿液中这些物质及其代谢物的检测窗口更长，这可能是由于母药在富含脂肪的组织中积累，并重新分布到循环系统和随后的新陈代谢。
In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D7.4 ranged from 2.81 (AB-FUBINACA) to 4.95 (MDMB-4en-PINACA) and all SCRAs tested were highly protein bound, ranging from 88.9 ± 0.49% ((R)-4F-MDMB-BINACA) to 99.5 ± 0.08% ((S)-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CLint) ranged from 13.7 ± 4.06 ((R)-AB-FUBINACA) to 2944 ± 95.9 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 ((S)-AB-FUBINACA) to 3216 ± 607 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CLH) ranged from 0.34 ± 0.09 ((S)-AB-FUBINACA) to 17.79 ± 0.20 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 ((S)-MDMB-FUBINACA) to 18.25 ± 0.12 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHHeps. Valinate and tert-leucinate indole and indazole-3-carboxamide SCRAs are often rapidly metabolised in vitro but are highly protein bound in vivo and therefore predicted in vivo CLH is much slower than CLint. This is likely to give rise to longer detection windows of these substances and their metabolites in urine, possibly as a result of accumulation of parent drug in lipid-rich tissues, with redistribution into the circulatory system and subsequent metabolism.
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影响因子：
2.9
作者：
Erratico, Claudio;Negreira, Noelia;van Nuijs, Alexander L. N.
通讯作者：
van Nuijs, Alexander L. N.
影响因子：
5.5
作者：
Antonides, Lysbeth H.;Cannaert, Annelies;McKenzie, Craig
通讯作者：
McKenzie, Craig
影响因子：
5.3
作者：
Carlier, Jeremy;Diao, Xingxing;Huestis, Marilyn A.
通讯作者：
Huestis, Marilyn A.
影响因子：
2.9
作者：
Antonides, Lysbeth H.;Cannaert, Annelies;McKenzie, Craig
通讯作者：
McKenzie, Craig
影响因子：
4.1
作者：
Doi, Takahiro;Asada, Akiko;Sawabe, Yoshiyuki
通讯作者：
Sawabe, Yoshiyuki