Intrinsic clearance rate of O-desmethyltramadol (M1) by glucuronide conjugation and phase I metabolism by feline, canine and common brush-tailed possum microsomes

Izes, Aaron M.; Kimble, Benjamin; Govendir, Merran

doi:10.1080/00498254.2019.1697014

Cited by 3 publications

(8 citation statements)

References 31 publications

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“…This study also demonstrated that mefloquine does not appear to undergo phase II conjugative glucuronidative metabolism when incubated by microsomes of cats, dogs and the common brush-tailed possum. Canine and common brush-tailed possum microsome incubations were used as the positive control for this phase II reaction as they have been shown to deplete ODMT to ODMT glucuronide [22]. This study supports the hypothesis that phase II conjugative metabolism may not be a route of mefloquine metabolism in any species.…”

Section: Plos Onesupporting

confidence: 64%

“…The rate of ODMT depletion over 180 mins with canine and possum microsomes was > 15% while the ODMT depletion with feline microsomes was not detected by HPLC. However, a small ODMT glucuronide signal was detected in the feline samples by LC-MS [22].…”

Section: Phase II Reactionmentioning

confidence: 94%

“…Negative controls underwent the incubation process described above and included one set that contained all incubation components except the substrate, another set which omitted the NADPH cofactors and another which omitted the microsomes. The positive control substrate was tramadol (1 μM tramadol incubated with 1.0 mg/mL of either feline microsomes or canine microsomes over 60 minutes) as it undergoes phase I metabolism to ODMT (M1) and to Ndesmethyltramadol (M2 or NDMT) when incubated with canine microsomes and to ODMT only when incubated with feline microsomes [22]. The tramadol samples did not undergo liquid-liquid extraction and no internal standard was used.…”

Section: Phase I Microsomal Incubationmentioning

confidence: 99%

“…Fluorescence detection (excitation: 200 nm / emission: 301 nm) was used. The total run time for each sample was 22.5 minutes and the retention times of ODMT and tramadol were approximately 6.7 and 17.2 minutes, respectively [22]. Each incubation was run in duplicate during a single experiment.…”

Section: Hplc Chromatographic Conditions For the Phase I And Phase Iimentioning

confidence: 99%

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In vitro hepatic metabolism of mefloquine using microsomes from cats, dogs and the common brush-tailed possum (Trichosurus vulpecula)

Izes¹,

Kimble²,

Norris³

et al. 2020

PLoS ONE

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Feline infectious peritonitis (FIP) is a systemic, fatal, viral-induced, immune-mediated disease of cats caused by feline infectious peritonitis virus (FIPV). Mefloquine, a human antimalarial agent, has been shown to inhibit FIPV in vitro. As a first step to evaluate its efficacy and safety profile as a potential FIP treatment for cats, mefloquine underwent incubation in feline, canine and common brush-tailed possum microsomes and phase I metabolism cofactors to determine its rate of phase I depletion. Tramadol was used as a phase I positive control as it undergoes this reaction in both dogs and cats. Using the substrate depletion method, the in vitro intrinsic clearance (mean ± S.D.) of mefloquine by pooled feline and common brush-tailed possum microsomes was 4.5 ± 0.35 and 18.25 ± 3.18 μL/min/mg protein, respectively. However, phase I intrinsic clearance was too slow to determine with canine microsomes. Liquid chromatography-mass spectrometry (LC-MS) identified carboxymefloquine in samples generated by feline microsomes as well as negative controls, suggesting some mefloquine instability. Mefloquine also underwent incubation with feline, canine and common brush-tailed possum microsomes and phase II glucuronidative metabolism cofactors. O-desmethyltramadol (ODMT or M1) was used as a positive control as it undergoes a phase II glucuronidation reaction in these species. The rates of phase II mefloquine depletion by microsomes by all three species were too slow to estimate. Therefore mefloquine likely undergoes phase I hepatic metabolism catalysed by feline and common brush-tailed possum microsomes but not phase II glucuronidative metabolism in all three species and mefloquine is not likely to have delayed elimination in cats with clinically normal, hepatic function. OPEN ACCESSCitation: Izes AM, Kimble B, Norris JM, Govendir M (2020) In vitro hepatic metabolism of mefloquine using microsomes from cats, dogs and the common brush-tailed possum (Trichosurus vulpecula). PLoS ONE 15(4): e0230975. https://doi.

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Section: Plos Onesupporting

confidence: 64%

Section: Phase II Reactionmentioning

confidence: 94%

Section: Phase I Microsomal Incubationmentioning

confidence: 99%

Section: Hplc Chromatographic Conditions For the Phase I And Phase Iimentioning

confidence: 99%

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In vitro hepatic metabolism of mefloquine using microsomes from cats, dogs and the common brush-tailed possum (Trichosurus vulpecula)

Izes¹,

Kimble²,

Norris³

et al. 2020

PLoS ONE

Self Cite

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“…Both chloroquine and mefloquine are commercially available pharmaceutical agents registered for use in people. Each has an extensive body of supporting literature regarding their pharmacokinetics and safety in non-feline species and some information is now available on mefloquine's pharmacokinetic profile in cats [77,78,79,80,81]. Considerably less is known about hexamethylene amiloride, particularly with respect to its safety [52].…”

Section: Other Antiviral Compoundsmentioning

confidence: 99%

Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats

Izes

Norris

et al. 2020

Veterinary Quarterly

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Feline infectious peritonitis (FIP) is a viral-induced, immune-mediated disease of cats caused by virulent biotypes of feline coronaviruses (FCoV), known as the feline infectious peritonitis virus (FIPV). Historically, three major pharmacological approaches have been employed to treat FIP: (1) immunomodulators to stimulate the patient's immune system non-specifically to reduce the clinical effects of the virus through a robust immune response, (2) immunosuppressive agents to dampen clinical signs temporarily, and (3) re-purposed human antiviral drugs, all of which have been unsuccessful to date in providing reliable efficacious treatment options for FIPV. Recently, antiviral studies investigating the broad-spectrum coronavirus protease inhibitor, GC376 and the adenosine nucleoside analogue GS-441524, have resulted in increased survival rates and clinical cure in many patients. However, prescriber access to these antiviral therapies is currently problematic as they have not yet obtained registration for veterinary use. Consequently, FIP remains challenging to treat. The purpose of this review is to provide an update on the current status of therapeutics for FIP. Additionally, due to interest in coronaviruses resulting from the current human pandemic, this review provides information on domesticated cats identified as SARS-CoV-2 positive.

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Clinical pharmacology of tramadol and tapentadol, and their therapeutic efficacy in different models of acute and chronic pain in dogs and cats

Domínguez-Oliva¹,

Casas-Alvarado²,

Miranda-Cortés³

et al. 2021

J Adv Vet Anim Res

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Opioids are considered the gold standard to manage acute or chronic or mild to severe pain. Tramadol is a widely prescribed analgesic drug for dogs and cats; it has a synthetic partial agonism on μ-opioid receptors and inhibits the reuptake of norepinephrine and serotonin. However, the biotransformation and resultant metabolites differ between species and depend on cytochrome P450 interactions. Dogs mainly produce the inactive N-desmethyl tramadol metabolite, whereas cats exhibit an improved antinociceptive effect owing to rapid active O-desmethyltramadol metabolite production and a longer elimination half-life. Tapentadol, a novel opioid with dual action on μ-receptors and noradrenaline reuptake inhibitory activity, is a promising option in dogs, as it is less reliant on metabolic activation and is unaffected by cytochrome polymorphisms. Although scientific evidence on the analgesic activity of tapentadol in both species remains limited, experimental studies indicate potential benefits in animals. This review summarizes and compares the pharmacology, pharmacokinetics, and therapeutic efficacy of tramadol and tapentadol in dogs and cats with different pain conditions. According to the available data, tramadol seems a more suitable therapeutic option for cats and should preferably be used as a component of multimodal analgesia in both species, particularly dogs. Tapentadol might possess a superior analgesic profile in small animals, but additional studies are required to comprehensively evaluate the activity of this opioid to manage pain in dogs and cats.

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Intrinsic clearance rate of O-desmethyltramadol (M1) by glucuronide conjugation and phase I metabolism by feline, canine and common brush-tailed possum microsomes

Cited by 3 publications

References 31 publications

In vitro hepatic metabolism of mefloquine using microsomes from cats, dogs and the common brush-tailed possum (Trichosurus vulpecula)

In vitro hepatic metabolism of mefloquine using microsomes from cats, dogs and the common brush-tailed possum (Trichosurus vulpecula)

Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats

Clinical pharmacology of tramadol and tapentadol, and their therapeutic efficacy in different models of acute and chronic pain in dogs and cats

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