Pharmacokinetics and pharmacodynamics of the synthetic cannabiniod UR-144 and its halogenated analogue 5F-UR-144 (XLR-11)


The new drug of abuse UR-144 and its halogenated form 5F-UR-144 (XLR-11) are potent alkylindole synthetic cannabinoids that have been recently identified in herbal mixtures with tobacco, incense and potpourri. In this presentation, the pharmacology, toxicokinetics and clinical effects of these drugs are reviewed. Information was searched in PubMed (U.S. National Library of Medicine) and governmental websites without limitation of the search period. Most data on UR-144 and XLR-11 come from clinical and forensic reports of intoxications. Although the mechanisms underlying their toxicity are not yet thoroughly documented, there is evidence of a considerable number of hospitalizations that resulted in fatal outcome following acute exposure. Intoxication symptoms include an increase in the muscular tonus, high systolic arterial pressure, anxiety, incoherent speech, impaired coordination, hallucinations, irritability, seizures, tachycardia and chest pain. Acute kidney injury (acute tubular injury and interstitial nephritis), pulmonary oedema, brain stroke and myocardial ischemia are frequently described in autopsies. UR-144 has great affinity for the CB2 receptor but substantial lower affinity for the CB1 receptor, while XLR-11 shows a potent agonist effect in both cannabinoid receptors. For XLR-11, the substitution of the fluorine atom by an hydroxyl group seems to be an important metabolic reaction, but several other metabolites co-occur for both drugs. Products of monohydroxylation, dihydroxylation and/or formation of the N-pentanoic acid were among the most abundant metabolites detected in human urine. UR-144 and XLR-11 are mainly metabolized at the hepatic level, especially by CYP3A4. However, it is presently unknown to which extent these metabolic reactions contribute to the (de)toxication of the drugs. The information is also scarce regarding the long-term effects of UR-144 and XLR-11 and their respective metabolites and how interindividual differences may influence their toxicity, hence further clinical and forensic toxicological studies are required.


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