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.
Publication Date: 2021-05-22 PubMed ID: 33978252PubMed Central: PMC8518386DOI: 10.1002/elps.202100115Google Scholar: Lookup
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Summary
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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
Researcher Affiliations
- Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
- Department for Horses, University of Leipzig, Leipzig, Germany.
- Clinical Unit of Anaesthesiology and Perioperative Intensive-Care Medicine, Vetmeduni Vienna, Vienna, Austria.
- Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
- Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
- 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
.
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