CYP2D6 phenotype explains reported yohimbine concentrations in four severe acute intoxications.
CYP2D6
Clearance
Modelling & simulation
Pharmacokinetics
Pharmacometrics
Yohimbine
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
13
04
2021
accepted:
17
05
2021
pubmed:
25
5
2021
medline:
12
1
2022
entrez:
24
5
2021
Statut:
ppublish
Résumé
The indole alkaloid yohimbine is an alpha-2 receptor antagonist used for its sympathomimetic effects. Several cases of yohimbine intoxication have been reported and the most recent one involved four individuals taking a yohimbine-containing drug powder. All individuals developed severe intoxication symptoms and were admitted to the hospital. Even though all individuals were assumed to have taken the same dose of the drug powder, toxicology analyses revealed yohimbine blood concentrations of 249-5631 ng/mL, amounting to a 22-fold difference. The reason for this high variability remained to be elucidated. We used recently reported knowledge on the metabolism of yohimbine together with state-of-the art nonlinear mixed-effects modelling and simulation and show that a patient's cytochrome P450 2D6 (CYP2D6) phenotype can explain the large differences observed in the measured concentration after intake of the same yohimbine dose. Our findings can be used both for the identification of safe doses in therapeutic use of yohimbine and for an explanation of individual cases of overdosing.
Identifiants
pubmed: 34027562
doi: 10.1007/s00204-021-03082-4
pii: 10.1007/s00204-021-03082-4
pmc: PMC8298364
doi:
Substances chimiques
Adrenergic alpha-2 Receptor Antagonists
0
Yohimbine
2Y49VWD90Q
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2867-2870Informations de copyright
© 2021. The Author(s).
Références
Anderson C, Anderson D, Harre N, Wade N (2013) Case study: two fatal case reports of acute yohimbine intoxication. J Anal Toxicol 37:611–614. https://doi.org/10.1093/jat/bkt057
doi: 10.1093/jat/bkt057
pubmed: 23846025
Bertilsson L, Lou YQ, Du YL et al (1992) Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 51:388–397. https://doi.org/10.1038/clpt.1992.38
doi: 10.1038/clpt.1992.38
pubmed: 1345344
Drevin G, Palayer M, Compagnon P et al (2020) A fatal case report of acute yohimbine intoxication. Forensic Toxicol 38:287–291. https://doi.org/10.1007/s11419-019-00512-y
doi: 10.1007/s11419-019-00512-y
Giampreti A, Lonati D, Locatelli C et al (2009) Acute neurotoxicity after yohimbine ingestion by a body builder. Clin Toxicol 47:827–829. https://doi.org/10.1080/15563650903081601
doi: 10.1080/15563650903081601
Gicquel T, Hugbart C, Le Devehat F et al (2016) Death related to consumption of Rauvolfia sp. powder mislabeled as Tabernanthe iboga. Forensic Sci Int 266:e38–e42. https://doi.org/10.1016/j.forsciint.2016.06.014
doi: 10.1016/j.forsciint.2016.06.014
pubmed: 27342343
Guthrie SK, Hariharan M, Grunhaus LJ (1990) Yohimbine bioavailability in humans. Eur J Clin Pharmacol 39:409–411. https://doi.org/10.1007/BF00315421
doi: 10.1007/BF00315421
pubmed: 2076728
Huddart R, Fohner AE, Whirl-Carrillo M et al (2019) Standardized biogeographic grouping system for annotating populations in pharmacogenetic research. Clin Pharmacol Ther 105:1256–1262. https://doi.org/10.1002/cpt.1322
doi: 10.1002/cpt.1322
pubmed: 30506572
Mueller-Schoell A, Michelet R, Klopp-Schulze L, van Dyk M, Mürdter TE, Schwab M, Joerger M, Huisinga W, Mikus G, Kloft C (2021) Computational treatment simulations to assess the need for personalized tamoxifen dosing in breast cancer patients of different biogeographical groups. Cancers 13:2432. https://doi.org/10.3390/cancers13102432
doi: 10.3390/cancers13102432
pubmed: 34069810
pmcid: 8157244
Nofziger C, Turner AJ, Sangkuhl K et al (2020) PharmVar GeneFocus: CYP2D6. Clin Pharmacol Ther 107:154–170. https://doi.org/10.1002/cpt.1643
doi: 10.1002/cpt.1643
pubmed: 31544239
Swann AC, Lijffijt M, Lane SD et al (2013) Norepinephrine and impulsivity: effects of acute yohimbine. Psychopharmacology 229:83–94. https://doi.org/10.1007/s00213-013-3088-7
doi: 10.1007/s00213-013-3088-7
pubmed: 23559222
pmcid: 3742556
Vay M, Meyer MJ, Blank A et al (2020) Oral Yohimbine as a new probe drug to predict CYP2D6 activity: results of a fixed-sequence phase I trial. Clin Pharmacokinet 59:927–939. https://doi.org/10.1007/s40262-020-00862-6
doi: 10.1007/s40262-020-00862-6
pubmed: 32060866
pmcid: 7329762
Wishart DS, Feunang YD, Guo AC et al (2018) DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res 46:D1074–D1082. https://doi.org/10.1093/nar/gkx1037
doi: 10.1093/nar/gkx1037
pubmed: 29126136
WebMD Yohimbe. https://www.webmd.com/vitamins/ai/ingredientmono-759/yohimbe . (Accessed 5 Mar 2021)
Zhu L, Han X, Zhu J et al (2021) Severe acute intoxication with yohimbine: four simultaneous poisoning cases. Forensic Sci Int. https://doi.org/10.1016/j.forsciint.2021.110705
doi: 10.1016/j.forsciint.2021.110705
pubmed: 33639417