Identification of detomidine carboxylic acid as the major urinary metabolite of detomidine in the horse

Salonen, Jarmo S.; Vuorilehto, Lauri; Gilbert, M. R.; Maylin, G. A.

doi:10.1007/bf03189982

Cited by 3 publications

(3 citation statements)

References 9 publications

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“…However, the lack of negative controls, which are recommended as part of investigations on phasic nociceptive testing (Slingsby 2010), and the inability to quantify the analgesic response limit the usefulness of their results.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have investigated the analgesic actions of detomidine (5–40 μg/kg intravenously) in donkeys (Mostafa and others 1995, El‐Maghraby and Atta 1997, EL‐Kammar and Gad 2014). However, the lack of negative controls, which are recommended as part of investigations on phasic nociceptive testing (Slingsby 2010), and the inability to quantify the analgesic response limit the usefulness of their results.…”

Section: Discussionmentioning

confidence: 99%

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Sedation and mechanical antinociception after intravenous administration of detomidine in donkeys: a dosage–effect study

et al. 2015

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There is limited, useful, scientific information on detomidine in donkeys. This study compared the effects of intravenous saline, detomidine (10, 13.5, 17 and 20 μg/kg) and acepromazine (50 μg/kg) in donkeys by computing areas under the curve for 0-30, 30-60 and 60-120 minutes (AUC0-30, AUC30-60 and AUC60-120) for sedation scores, head heights and mechanical nociceptive thresholds (MNTs). For sedation scores, all detomidine treatments, except 10 μg/kg, increased AUC0-30 values compared with saline, and AUC0-30 values were larger for 17 μg/kg detomidine than for acepromazine. All head height AUC values were lower for detomidine than for saline (except AUC60-120 for 10 μg/kg detomidine) and acepromazine (except AUC0-30 for 10 and 20 μg/kg detomidine, and AUC60-120 for 10 μg/kg detomidine). For MNTs, all detomidine treatments increased AUC0-30 and AUC30-60 values compared with saline and acepromazine; AUC30-60 values were smaller for 10 μg/kg than for 17 and 20 μg/kg detomidine. MNT AUC60-120 values were larger for 20 μg/kg detomidine than for saline, 10 μg/kg detomidine and acepromazine. Detomidine induced sedation and antinociception, but only antinociception was dosage dependent. Selection of detomidine dosage for donkeys may depend on the required duration of sedation and/or degree of analgesia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sedation and mechanical antinociception after intravenous administration of detomidine in donkeys: a dosage–effect study

et al. 2015

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“…Sequential oxidation of a methyl group to form hydroxymethyl and carboxylic acid metabolites is a known pathway in drug metabolism and, indeed, hydroxymethyl metabolites of a number of drugs are known to be readily oxidised to form carboxylic acids in man and horse 44–48. Sequential oxidation of the 17α‐ethyl group of norethandrolone in the horse, to form 1‐hydroxyethyl metabolites, and further oxidation of the side chain to carboxylic acid metabolites have been reported 28.…”

Section: Resultsmentioning

confidence: 99%

In vivo biotransformation of 17α‐methyltestosterone in the horse revisited: identification of 17‐hydroxymethyl metabolites in equine urine by capillary gas chromatography/mass spectrometry

Dumasia¹

2003

Rapid Comm Mass Spectrometry

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The in vivo phase I biotransformation of 17 alpha-methyltestosterone in the horse leads to the formation of a complex mixture of regio- and stereoisomeric C(20)O(2), C(20)O(3) and C(20)O(4) metabolites, excreted in urine as glucuronide and sulphate phase II conjugates. The major pathways of in vivo metabolism are the reduction of the A-ring (di- and tetrahydro), epimerisation at C-17 and oxidations mainly at C-6 and C-16. Some phase I metabolites have been identified previously by positive ion electron ionisation capillary gas chromatography/mass spectrometry (GC/EI + MS) mainly from the characteristic fragmentation patterns of their methyloxime-trimethylsilyl ether (MO-TMS), enol-TMS or TMS ether derivatives. Following oral administration of 17 alpha-methyltestosterone to two castrated thoroughbred male horses, the glucuronic acid conjugates excreted in post-administration urine samples were selectively hydrolysed by E. coli beta-glucuronidase enzymes. Unconjugated metabolites and the steroid aglycones obtained after enzymatic deconjugation were isolated from urine by solid-phase extraction, derivatised as MO-TMS ethers and analysed by GC/EI + MS. In addition to some of the known metabolites previously identified from the characteristic mass spectral fragmentation patterns of 17 alpha-methyl steroids, some isobaric compounds exhibiting a diagnostic loss of 103 mass units from the molecular ions with subsequent losses of trimethylsilanol or methoxy groups and an absence of the classical D-ring fragment ion were detected. From an interpretation of their mass spectra, these compounds were identified as 17-hydroxymethyl metabolites, formed in vivo in the horse by oxidation of the 17-methyl moiety of 17 alpha-methyltestosterone. This study reports on the GC/EI + MS identification of these novel 17-hydroxymethyl C(20)O(3) and C(20)O(4) metabolites of 17 alpha-methyltestosterone excreted in thoroughbred horse urine.

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Drug metabolism in the horse: a review

Scarth

Teale

Kuuranne

2010

Drug Testing and Analysis

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A detailed understanding of equine drug metabolism is important for detection of drug abuse in horseracing and also in veterinary drug development and practice. To date, however, no comprehensive review of equine drug metabolism has been published. The majority of literature regarding equine drug metabolite profiles is derived from sports drug detection research and is generally targeted at detecting marker metabolites of drug abuse. However, the bulk of the literature on equine drug metabolism enzymology is derived from veterinary studies aimed at determining the molecular basis of metabolism. In this article, the phase 1 and 2 metabolisms of seven of the most important classes of drugs monitored in horseracing are reviewed, including: anabolic-androgenic steroids (AAS), β₂ -agonists, stimulants, sedatives/tranquilizers, local anesthetics, non-steroidal anti-inflammatory analgesics (NSAIDS)/cyclooxygenase-2 (COX-2) inhibitors, and opioid analgesics. A summary of the literature relating to the enzymology of drug metabolism in this species is also be presented. The future of equine drug metabolism in the area of doping research will be influenced by several factors, including: a possible move towards the increased use of blood and other alternative testing matrices; the development of assays based on intact drug conjugates; the increasing threat of 'designer' and herbal- based products; advances in the use of in vitro technologies; the increased use of liquid-chromatography/high-resolution mass spectrometry; and the possibility of screening using 'omics' approaches. Also, the recent cloning of a range of equine cytochrome P450 (CYP) enzymes opens up the potential for carrying out more detailed mechanistic pharmacological and toxicological veterinary studies.

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Identification of detomidine carboxylic acid as the major urinary metabolite of detomidine in the horse

Cited by 3 publications

References 9 publications

Sedation and mechanical antinociception after intravenous administration of detomidine in donkeys: a dosage–effect study

Sedation and mechanical antinociception after intravenous administration of detomidine in donkeys: a dosage–effect study

In vivo biotransformation of 17α‐methyltestosterone in the horse revisited: identification of 17‐hydroxymethyl metabolites in equine urine by capillary gas chromatography/mass spectrometry

Drug metabolism in the horse: a review

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