FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Electrophoresis2021; 42(17-18); 1826-1831; doi: 10.1002/elps.202100115

Stereoselective methadone disposition after administration of racemic methadone to anesthetized Shetland ponies assessed by capillary electrophoresis.

Abstract: The enantioselectivity of the pharmacokinetics of methadone was investigated in anesthetized Shetland ponies after a single intravenous (0.5 mg/kg methadone hydrochloride; n = 6) or constant rate infusion (0.25 mg/kg bolus followed by 0.25 mg/kg/h methadone hydrochloride; n = 3) administration of racemic methadone. Plasma concentrations of l-methadone and d-methadone and their major metabolites, l- and d-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), respectively, were analyzed by CE with highly sulfated γ-cyclodextrin as chiral selector and electrokinetic analyte injection from liquid/liquid extracts prepared at alkaline pH. In both trials, the d-methadone concentrations were lower than those of l-methadone and the d-EDDP levels were lower than those of L-EDDP. For the case of a single intravenous bolus injection, the plasma concentration versus time profile of methadone enantiomers was analyzed with a two-compartment pharmacokinetic model. l-methadone showed a slower elimination rate constant, a lower body clearance, and a smaller steady-state volume of distribution than d-methadone. d-methadone and d-EDDP were eliminated faster than their respective l-enantiomers. This is the first study that outlines that the disposition of racemic methadone administered to anesthetized equines is enantioselective.
© 2021 The Authors. Electrophoresis published by Wiley-VCH GmbH.
Get Full Text
Publication Date: 2021-05-22 PubMed ID: 33978252PubMed Central: PMC8518386DOI: 10.1002/elps.202100115Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research study explores the difference in breakdown and clearance (pharmacokinetics) of the two mirror image forms (enantiomers) of methadone, a pain medication, in sedated Shetland ponies. The results reveal a preferential breakdown and clearance of one form over the other.

Introduction to the Research

  • This study investigates the stereoselective (preferential) pharmacokinetics of methadone in sedated Shetland ponies.
  • The methadone administered was racemic, meaning it contained equal amounts of the two enantiomers – l-methadone and d-methadone. Enantiomers are molecules that are mirror images of each other and often have different properties.
  • Both a single dose and a constant-rate infusion were tested to allow for comparison in the body’s response.

Research Methodology

  • After methadone administration, plasma concentrations of both l-methadone and d-methadone, as well as their major metabolites (substances produced during metabolism), were analysed.
  • The analysis was performed with the help of capillary electrophoresis using sulfated γ-cyclodextrin as a chiral selector – a compound that helps differentiate between mirror image molecules.

Results and Findings

  • In both research scenarios, the levels of d-methadone and its metabolite, d-EDDP, were found to be lower than those of l-methadone and its metabolite, l-EDDP. This indicated a faster breakdown and clearance of the d-forms.
  • For a single dose administration, the l-methadone demonstrated slower clearance rates and a smaller distribution volume than d-methadone, suggesting a slower rate of metabolism and elimination.
  • d-methadone and d-EDDP were eliminated faster than their l-enantiomers, indicating faster metabolism and elimination rates for the d-forms.

Conclusion

  • The study hence highlighted that the breakdown and clearance (disposition) of methadone in sedated ponies is enantioselective, meaning that it prefers one mirror image molecule over the other.
  • This could inform the understanding of the drug’s effects and the development of methadone dosing strategies in equine veterinary medicine.

Cite This Article

APA
Sandbaumhüter FA, Gittel C, Larenza-Menzies MP, Theurillat R, Thormann W, Braun C. (2021). Stereoselective methadone disposition after administration of racemic methadone to anesthetized Shetland ponies assessed by capillary electrophoresis. Electrophoresis, 42(17-18), 1826-1831. https://doi.org/10.1002/elps.202100115

Publication

Electrophoresis
ISSN: 1522-2683
NlmUniqueID: 8204476
Country: Germany
Language: English
Volume: 42
Issue: 17-18
Pages: 1826-1831

Researcher Affiliations

Sandbaumhüter, Friederike A
  • Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
Gittel, Claudia
  • Department for Horses, University of Leipzig, Leipzig, Germany.
Larenza-Menzies, M Paula
  • Clinical Unit of Anaesthesiology and Perioperative Intensive-Care Medicine, Vetmeduni Vienna, Vienna, Austria.
Theurillat, Regula
  • Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
Thormann, Wolfgang
  • Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
Braun, Christina
  • Clinical Unit of Anaesthesiology and Perioperative Intensive-Care Medicine, Vetmeduni Vienna, Vienna, Austria.

MeSH Terms

  • Animals
  • Electrophoresis, Capillary
  • Horses
  • Methadone
  • Pyrrolidines
  • Stereoisomerism

Conflict of Interest Statement

.

References

This article includes 33 references
  1. Gozalo-Marcilla M, Gasthuys F, Schauvliege S. Partial intravenous anaesthesia in the horse: a review of intravenous agents used to supplement equine inhalation anaesthesia. Part 2: opioids and alpha-2 adrenoceptor agonists.. Vet Anaesth Analg 2015 Jan;42(1):1-16.
    pubmed: 24984895doi: 10.1111/vaa.12196google scholar: lookup
  2. Inturrisi CE. Pharmacology of methadone and its isomers.. Minerva Anestesiol 2005 Jul-Aug;71(7-8):435-7.
    pubmed: 16012416
  3. Robertson SA. Standing sedation and pain management for ophthalmic patients.. Vet Clin North Am Equine Pract 2004 Aug;20(2):485-97.
    pubmed: 15271436doi: 10.1016/j.cveq.2004.04.005google scholar: lookup
  4. Robertson SA, Taylor PM. Pain management in cats--past, present and future. Part 2. Treatment of pain--clinical pharmacology.. J Feline Med Surg 2004 Oct;6(5):321-33.
    pubmed: 15363764doi: 10.1016/j.jfms.2003.10.002google scholar: lookup
  5. Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine.. Life Sci 1995;56(2):PL45-50.
    pubmed: 7823756doi: 10.1016/0024-3205(94)00426-sgoogle scholar: lookup
  6. Ferrari A, Coccia CP, Bertolini A, Sternieri E. Methadone--metabolism, pharmacokinetics and interactions.. Pharmacol Res 2004 Dec;50(6):551-9.
    pubmed: 15501692doi: 10.1016/j.phrs.2004.05.002google scholar: lookup
  7. Garrido MJ, Trocóniz IF. Methadone: a review of its pharmacokinetic/pharmacodynamic properties.. J Pharmacol Toxicol Methods 1999 Oct;42(2):61-6.
    pubmed: 10924887doi: 10.1016/s1056-8719(00)00043-5google scholar: lookup
  8. Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19.. Chirality 2004 Jan;16(1):36-44.
    pubmed: 14628297doi: 10.1002/chir.10303google scholar: lookup
  9. Kharasch ED, Stubbert K. Role of cytochrome P4502B6 in methadone metabolism and clearance.. J Clin Pharmacol 2013 Mar;53(3):305-13.
    pmc: PMC3743098pubmed: 23361846doi: 10.1002/jcph.1google scholar: lookup
  10. Kristensen K, Blemmer T, Angelo HR, Christrup LL, Drenck NE, Rasmussen SN, Sjøgren P. Stereoselective pharmacokinetics of methadone in chronic pain patients.. Ther Drug Monit 1996 Jun;18(3):221-7.
    pubmed: 8738759doi: 10.1097/00007691-199606000-00001google scholar: lookup
  11. Schmidt N, Brune K, Williams KM, Geisslinger G. Stereoselective pharmacokinetics of methadone in beagle dogs.. Chirality 1994;6(6):492-5.
    pubmed: 7946975doi: 10.1002/chir.530060608google scholar: lookup
  12. Crosignani N, Luna SP, Dalla Costa T, Pimenta EL, Detoni CB, Guterres SS, Puoli Filho JN, Pantoja JC, Pigatto MC. Pharmacokinetics and pharmacodynamics of the injectable formulation of methadone hydrochloride and methadone in lipid nanocarriers administered orally to horses.. J Vet Pharmacol Ther 2017 Aug;40(4):398-405.
    pubmed: 28092108doi: 10.1111/jvp.12393google scholar: lookup
  13. Linardi RL, Stokes AM, Keowen ML, Barker SA, Hosgood GL, Short CR. Bioavailability and pharmacokinetics of oral and injectable formulations of methadone after intravenous, oral, and intragastric administration in horses.. Am J Vet Res 2012 Feb;73(2):290-5.
    pubmed: 22280392doi: 10.2460/ajvr.73.2.290google scholar: lookup
  14. Hadley MR, Camilleri P, Hutt AJ. Enantiospecific analysis by capillary electrophoresis: applications in drug metabolism and pharmacokinetics.. Electrophoresis 2000 Jun;21(10):1953-76.
    pubmed: 10879955doi: 10.1002/1522-2683(20000601)21:10<1953::aid-elps1953>3.0.co;2-ggoogle scholar: lookup
  15. Bonato PS. Recent advances in the determination of enantiomeric drugs and their metabolites in biological fluids by capillary electrophoresis-mediated microanalysis.. Electrophoresis 2003 Dec;24(22-23):4078-94.
    pubmed: 14661235doi: 10.1002/elps.200305632google scholar: lookup
  16. Caslavska J, Thormann W. Stereoselective determination of drugs and metabolites in body fluids, tissues and microsomal preparations by capillary electrophoresis (2000-2010).. J Chromatogr A 2011 Jan 28;1218(4):588-601.
    pubmed: 20869061doi: 10.1016/j.chroma.2010.08.072google scholar: lookup
  17. Sánchez-Hernández L, Guijarro-Diez M, Marina ML, Crego AL. New approaches in sensitive chiral CE.. Electrophoresis 2014 Jan;35(1):12-27.
    pubmed: 24132619doi: 10.1002/elps.201300355google scholar: lookup
  18. Caslavska J, Thormann W. Bioanalysis of drugs and their metabolites by chiral electromigration techniques (2010-2020).. Electrophoresis 2021 Sep;42(17-18):1744-1760.
    pubmed: 33570170doi: 10.1002/elps.202000383google scholar: lookup
  19. Theurillat R, Sandbaumhüter FA, Gittel C, Larenza Menzies MP, Braun C, Thormann W. Enantioselective capillary electrophoresis for pharmacokinetic analysis of methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in equines anesthetized with ketamine and isoflurane.. Electrophoresis 2019 Aug;40(15):1959-1965.
    pubmed: 30900259doi: 10.1002/elps.201900044google scholar: lookup
  20. Schappler J, Guillarme D, Prat J, Veuthey JL, Rudaz S. Validation of chiral capillary electrophoresis-electrospray ionization-mass spectrometry methods for ecstasy and methadone in plasma.. Electrophoresis 2008 May;29(10):2193-202.
    pubmed: 18409162doi: 10.1002/elps.200700464google scholar: lookup
  21. Theurillat R, Sandbaumhüter FA, Bettschart-Wolfensberger R, Thormann W. Microassay for ketamine and metabolites in plasma and serum based on enantioselective capillary electrophoresis with highly sulfated γ-cyclodextrin and electrokinetic analyte injection.. Electrophoresis 2016 May;37(9):1129-38.
    pubmed: 26626946doi: 10.1002/elps.201500468google scholar: lookup
  22. Sandbaumhüter FA, Theurillat R, Bektas RN, Kutter APN, Bettschart-Wolfensberger R, Thormann W. Pharmacokinetics of ketamine and three metabolites in Beagle dogs under sevoflurane vs. medetomidine comedication assessed by enantioselective capillary electrophoresis.. J Chromatogr A 2016 Oct 7;1467:436-444.
    pubmed: 27485149doi: 10.1016/j.chroma.2016.07.060google scholar: lookup
  23. Gittel C, Schulz-Kornas E, Sandbaumhüter FA, Theurillat R, Vervuert I, Larenza Menzies MP, Thormann W, Braun C. Pharmacokinetics and pharmacodynamics of l-methadone in isoflurane-anaesthetized and mechanically ventilated ponies.. Vet Anaesth Analg 2021 Mar;48(2):213-222.
    pubmed: 33423953doi: 10.1016/j.vaa.2020.04.018google scholar: lookup
  24. Carregaro AB, Freitas GC, Ribeiro MH, Xavier NV, Dória RG. Physiological and analgesic effects of continuous-rate infusion of morphine, butorphanol, tramadol or methadone in horses with lipopolysaccharide (LPS)-induced carpal synovitis.. BMC Vet Res 2014 Dec 21;10:966.
    pmc: PMC4297404pubmed: 25528353doi: 10.1186/s12917-014-0299-zgoogle scholar: lookup
  25. Gibaldi, M. , Perrier, D. , Pharmacokinetics, 2nd ed., Marcel Dekker Inc., New York: 1982.
  26. Yamaoka K, Nakagawa T, Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations.. J Pharmacokinet Biopharm 1978 Apr;6(2):165-75.
    pubmed: 671222doi: 10.1007/bf01117450google scholar: lookup
  27. Boulton DW, Arnaud P, DeVane CL. Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate.. Clin Pharmacol Ther 2001 Jul;70(1):48-57.
    pubmed: 11452244doi: 10.1067/mcp.2001.116793google scholar: lookup
  28. Sharma A, Tallchief D, Blood J, Kim T, London A, Kharasch ED. Perioperative pharmacokinetics of methadone in adolescents.. Anesthesiology 2011 Dec;115(6):1153-61.
    pmc: PMC3560937pubmed: 22037641doi: 10.1097/aln.0b013e318238fec5google scholar: lookup
  29. Eap CB, Cuendet C, Baumann P. Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha 1-acid glycoprotein.. Clin Pharmacol Ther 1990 Mar;47(3):338-46.
    pubmed: 2311335doi: 10.1038/clpt.1990.37google scholar: lookup
  30. Kharasch ED. Current Concepts in Methadone Metabolism and Transport.. Clin Pharmacol Drug Dev 2017 Mar;6(2):125-134.
    pmc: PMC6339814pubmed: 28263461doi: 10.1002/cpdd.326google scholar: lookup
  31. Wang SC, Ho IK, Wu SL, Liu SC, Kuo HW, Lin KM, Liu YL. Development of a method to measure methadone enantiomers and its metabolites without enantiomer standard compounds for the plasma of methadone maintenance patients.. Biomed Chromatogr 2010 Jul;24(7):782-8.
    pubmed: 19904716doi: 10.1002/bmc.1363google scholar: lookup
  32. Peters LM, Demmel S, Pusch G, Buters JT, Thormann W, Zielinski J, Leeb T, Mevissen M, Schmitz A. Equine cytochrome P450 2B6--genomic identification, expression and functional characterization with ketamine.. Toxicol Appl Pharmacol 2013 Jan 1;266(1):101-8.
    pubmed: 23142468doi: 10.1016/j.taap.2012.10.028google scholar: lookup
  33. Carlquist JF, Moody DE, Knight S, Johnson EG, Fang WB, Huntinghouse JA, Rollo JS, Webster LR, Anderson JL. A Possible Mechanistic Link Between the CYP2C19 Genotype, the Methadone Metabolite Ethylidene-1,5-Dimethyl-3,3-Diphenylpyrrolidene (EDDP), and Methadone-Induced Corrected QT Interval Prolongation in a Pilot Study.. Mol Diagn Ther 2015 Apr;19(2):131-8.
    pubmed: 25903311doi: 10.1007/s40291-015-0137-4google scholar: lookup

Citations

This article has been cited 1 times.
  1. Ma Y, Hu Y, Zheng L, Chen L, Zhao X, Qu F. [Annual review of capillary electrophoresis technology in 2021]. Se Pu 2022 Jul;40(7):591-599.
    doi: 10.3724/SP.J.1123.2022.03040pubmed: 35791597google scholar: lookup
Subscribe to our newsletter
Join 99,727 horse owners like you who receive our email updates on horse health and nutrition.