Characterization of the pharmacokinetics, behavioral effects and effects on thermal nociception of morphine 6-glucuronide and morphine 3-glucuronide in horses

Knych, Heather K.; Kanarr, Kirsten L.; Fang, Yong; McKemie, Daniel S.; Kass, Philip H.

doi:10.1016/j.vaa.2022.07.006

Cited by 7 publications

(30 citation statements)

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“…administration of 0.2 mg/kg morphine (Dönselmann Im Sande et al, 2017). This finding combined with reports of an anti‐nociceptive effect following administration of M6G to horses (Knych et al, 2022), suggest that the concentrations of M6G achieved following oral administration of 0.6 and 0.8 mg/kg morphine may have an anti‐nociceptive effect.…”

Section: Discussionsupporting

confidence: 71%

“…As reported previously, locomotor activity, reflected as circling behavior and an increase in the number of steps taken, increased following i.v. administration (Combie et al, 1981; Hamamoto‐Hardman et al, 2019; Knych et al, 2014, 2022). In the oral dosing groups, step counts were either not significantly different or decreased, relative to baseline.…”

Section: Discussionmentioning

confidence: 99%

“…In a study conducted previously by our laboratory, we demonstrated that M6G administration resulted in a thermal anti‐nociceptive effect following intravenous (i.v.) administration to horses, without significant adverse effects (Knych et al, 2022). While notably the number of animals studied was small ( n = 7) and a single dose studied, findings from this study suggest that, like other species, M6G has a favorable pharmacodynamic effect in horses (Knych et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…administration to horses, without significant adverse effects (Knych et al, 2022). While notably the number of animals studied was small ( n = 7) and a single dose studied, findings from this study suggest that, like other species, M6G has a favorable pharmacodynamic effect in horses (Knych et al, 2022). Furthermore, administration of a single dose of M3G to a small group of horses ( n = 4) did not appear to elicit neuroexcitation as has been reported in other species, suggesting that perhaps morphine is responsible for these effects in horses.…”

Section: Introductionmentioning

confidence: 99%

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Concentrations, pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites following oral administration to horses

Poth

McKemie

Traynham

et al. 2023

Vet Pharm & Therapeutics

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The metabolism and pharmacokinetics of intravenous (i.v.) morphine in the horse have been described; however, administration of therapeutic doses has also been associated with neuroexcitation and adverse gastrointestinal effects. In this study, we hypothesized that oral administration would lead to comparable concentrations of morphine and its presumed active metabolite, morphine 6-glucuronide (M6G) without the adverse effects associated with i.v. administration. Eight horses were administered a single i.v. dose of 0.2 mg/kg morphine and oral doses of 0.2, 0.6, and 0.8 mg/ kg of morphine in a four-way balanced crossover design, with a 2-week washout period between doses. Concentrations of morphine and metabolites were determined, and pharmacokinetic parameters determined. Physiologic and behavioral outcomes including the number of steps taken, changes in heart rate, and gastrointestinal borborygmi were assessed. Oral administration of morphine resulted in higher concentrations of morphine metabolites, including M6G (C max : 11.6-37.8 ng/mL (0.6 mg/ kg); 15.8-42.6 ng/mL (0.8 mg/kg)), compared with i.v. Bioavailability was 36.5%, 27.6% and 28.0% for 0.2, 0.6 and 0.8 mg/kg, respectively. Behavioral and physiologic changes were noted in all groups but were less prominent with oral compared with i.v. administration. Results of the current study are encouraging for further study, specifically anti-nociceptive effects of morphine following oral administration.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Concentrations, pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites following oral administration to horses

Poth

McKemie

Traynham

et al. 2023

Vet Pharm & Therapeutics

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“…It is unknown if H3G has analgesic effects; however, the structural analog M3G has been associated with neuroexcitant signs in rats without analgesic effects. In contrast, the morphine metabolite morphine-6-glucuronide has been associated with analgesic effects, 20,42 but an analgesic analog metabolite has not been identified for hydromorphone. A study 41 investigating the neuroexcitant effects of H3G in rats revealed that it can induce dose-dependent-excitatory behaviors such as myoclonus, changes in body postures, and tonic-clonic seizures.…”

Section: Discussionmentioning

confidence: 99%

High bioavailability, short half-life, and metabolism into hydromorphone-3-glucuronide following single intramuscular and intravenous administration of hydromorphone hydrochloride to great horned owls (Bubo virginianus)

Sosa-Higareda

Guzmán

Knych

et al. 2023

ajvr

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OBJECTIVE To determine the pharmacokinetic parameters of hydromorphone hydrochloride and its metabolite, hydromorphone-3-glucuronide (H3G), after a single IV and IM dose in great horned owls (Bubo virginianus). ANIMALS 6 healthy adult great horned owls (3 females and 3 males). PROCEDURES A single dose of hydromorphone (0.6 mg/kg) was administered once IM (pectoral muscles) and IV (left jugular) with a 6-week washout period between experiments. Blood samples were collected at 5 minutes and 0.5, 1.5, 2, 3, 6, 9, and 12 hours after drug administration. Plasma hydromorphone and H3G concentrations were determined with liquid chromatography–tandem mass spectrometry, and a noncompartmental analysis was used for the determination of pharmacokinetic parameters. RESULTS Hydromorphone had a high bioavailability of 170.8 ± 37.6% and rapid elimination after IM administration and rapid plasma clearance and a large volume of distribution after IV administration. Mean Cmax was 225.46 ± 0.2 ng/mL at 13 minutes after IM injection. Mean volume of distribution and plasma drug clearance was 4.29 ± 0.5 L/kg and 62.11 ± 14.6 mL/min/kg, respectively, after IV administration. Mean t1/2 was 1.62 ± 0.36 and 1.35 ± 0.59 hours after IM and IV administration, respectively. The metabolite H3G was readily measured shortly after administration by both routes. CLINICAL RELEVANCE A single dose of 0.6 mg/kg was well tolerated in all birds. Hydromorphone rapidly attained plasma concentrations following IM administration and had high bioavailability and short t1/2. This study is the first to document the presence of the metabolite H3G in avian species, which suggests similar hydromorphone metabolism as in mammals.

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Endogenous opiates and behavior: 2022

Bodnar

2023

Peptides

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Characterization of the pharmacokinetics, behavioral effects and effects on thermal nociception of morphine 6-glucuronide and morphine 3-glucuronide in horses

Cited by 7 publications

References 30 publications

Concentrations, pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites following oral administration to horses

Concentrations, pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites following oral administration to horses

High bioavailability, short half-life, and metabolism into hydromorphone-3-glucuronide following single intramuscular and intravenous administration of hydromorphone hydrochloride to great horned owls (Bubo virginianus)

Endogenous opiates and behavior: 2022

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