title: Studies on the metabolism of the fentanyl-derived designer drug butyrfentanyl in human in vitro liver preparations and authentic human samples using liquid chromatography-high resolution mass spectrometry (LC-HRMS).
abstract: Increasing numbers of new psychoactive substances (NPS) among them fentanyl derivatives has been reported by the European monitoring centre for drugs and drug addiction (EMCDDA). Butyrfentanyl is a new fentanyl derivative whose potency ratio was found to be seven compared to morphine and 0.13 compared to fentanyl. Several case reports on butyrfentanyl intoxications have been described. Little is known about its pharmacokinetic properties including its metabolism. However, knowledge of metabolism is essential for analytical detection in clinical and forensic toxicology. Therefore, in vitro and in vivo phase I and phase II metabolites of butyrfentanyl were elucidated combining liquid chromatography with a qTOF high resolution mass spectrometer. Human liver microsomes and recombinant cytochrome P450 enzymes (CYP) were used for in vitro assays. Authentic blood and urine samples from a fatal intoxication case were available for in vivo comparison. Butyrfentanyl was shown to undergo extensive metabolism. Six pathways could be postulated with hydroxylation and N-dealkylation being the major ones in vitro. In vivo, hydroxylation of the butanamide side chain followed by subsequent oxidation to the carboxylic acid represented the major metabolic step in the authentic case. Initial screening experiments with the most relevant CYPs indicated that mainly CYP2D6 and 3A4 were involved in the primary metabolic steps. Altered CYP2D6 and CYP3A4 status might cause a different metabolite pattern, making the inclusion of metabolites of different pathways recommendable when applying targeted screening procedures in clinical and forensic toxicology. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Switzerland.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Steuer
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Williner
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Switzerland.
authors.forename: Sandra N
authors.initials: SN
authors.lastname: Staeheli
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kraemer
mesh_terms: D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002853:Chromatography, Liquid / Q000379:methods; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015198:Designer Drugs / Q000378:metabolism* / Q000493:pharmacokinetics; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D053858:Metabolic Networks and Pathways; D008862:Microsomes, Liver / Q000378:metabolism*
chemical_list: D015198:Designer Drugs; C000610976:butyrfentanyl; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D005283:Fentanyl
keywords: Butyrfentanyl; CYP isoenzymes; Human liver microsomes; LC-HRMS; metabolism