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Metabolism of Carfentanil, an Ultra-Potent Opioid, in Human Liver Microsomes and Human Hepatocytes by High-Resolution Mass Spectrometry
US Army, MD 21010 USA.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. NIDA, MD 21224 USA; National Board Forens Med, Department Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
Excet Inc, VA 22150 USA.
SCIEX Ltd, CA 94404 USA.
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2016 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 18, no 6, 1489-1499 p.Article in journal (Refereed) Published
Abstract [en]

Carfentanil is an ultra-potent synthetic opioid. No human carfentanil metabolism data are available. Reportedly, Russian police forces used carfentanil and remifentanil to resolve a hostage situation in Moscow in 2002. This alleged use prompted interest in the pharmacology and toxicology of carfentanil in humans. Our study was conducted to identify human carfentanil metabolites and to assess carfentanils metabolic clearance, which could contribute to its acute toxicity in humans. We used Simulations Pluss ADMET Predictor (TM) and Molecular Discoverys MetaSite (TM) to predict possible metabolite formation. Both programs gave similar results that were generally good but did not capture all metabolites seen in vitro. We incubated carfentanil with human hepatocytes for up to 1 h and analyzed samples on a Sciex 3200 QTRAP mass spectrometer to measure parent compound depletion and extrapolated that to represent intrinsic clearance. Pooled primary human hepatocytes were then incubated with carfentanil up to 6 h and analyzed for metabolite identification on a Sciex 5600+ TripleTOF (QTOF) high-resolution mass spectrometer. MS and MS/MS analyses elucidated the structures of the most abundant metabolites. Twelve metabolites were identified in total. N-Dealkylation and monohydroxylation of the piperidine ring were the dominant metabolic pathways. Two N-oxide metabolites and one glucuronide metabolite were observed. Surprisingly, ester hydrolysis was not a major metabolic pathway for carfentanil. While the human liver microsomal system demonstrated rapid clearance by CYP enzymes, the hepatocyte incubations showed much slower clearance, possibly providing some insight into the long duration of carfentanils effects.

Place, publisher, year, edition, pages
SPRINGER , 2016. Vol. 18, no 6, 1489-1499 p.
Keyword [en]
carfentanil; metabolism; norcarfentanil; opioid
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-132994DOI: 10.1208/s12248-016-9963-5ISI: 000387547000015PubMedID: 27495118OAI: oai:DiVA.org:liu-132994DiVA: diva2:1054705
Note

Funding Agencies|Defense Threat Reduction Agency (DTRA) [CB3281]

Available from: 2016-12-09 Created: 2016-12-07 Last updated: 2016-12-09

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CiteExportLink to record
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Citation style
  • apa
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