Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study

Giorgi, Mario; Saccomanni, Giuseppe; Łebkowska‐Wieruszewska, Beata; Kowalski, C.

doi:10.1016/j.tvjl.2007.12.011

Cited by 49 publications

(38 citation statements)

References 7 publications

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“…These differences in absorption rate and C max could be triggered by a different oral bioavailability, reported as 98% in humans, but never tested in dogs. In agreement with this speculation, earlier studies reported a drastic reduction of drug oral bioavailability in dogs when compared to humans (Giorgi et al 2009.…”

Section: Discussionsupporting

confidence: 74%

Pharmacokinetics and pharmacodynamics (PK/PD) of irbesartan in Beagle dogs after oral administration at two dose rates

Carlucci¹,

Song²,

Yun³

et al. 2013

Polish Journal of Veterinary Sciences

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Irbesartan (Irb) is an angiotensin II type 1 receptor antagonist widely used in humans to treat hypertension. Age-related diseases such as hypertension are increasingly being diagnosed in dogs and there is the need for new drugs. The PK/PD of Irb was tested in Beagle dogs. Ten healthy Beagles were orally administered two dose rates (2 and 5 mg/kg), according to a cross over study design. Blood collections for PK analysis and systolic blood pressure (SBP), heart and respiratory rate, mucous membranes colour, capillary refill time and temperature evaluations were performed at scheduled intervals. The drug plasma concentration was dose dependent. The dogs administered 5 mg/kg showed a significant reduction in SBP, while in those receiving 2 mg/kg, this parameter was minimally affected. A counter clockwise hysteresis showed no direct correlation between SBP and plasma concentrations. The minimum effective concentration was theorized to be within the range 550-800 ng/mL. Although further studies are necessary, 5 mg/kg seems to be the more appropriate dose to obtain a hypotensive effect in Beagle dogs.

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Section: Discussionsupporting

confidence: 74%

Pharmacokinetics and pharmacodynamics (PK/PD) of irbesartan in Beagle dogs after oral administration at two dose rates

Carlucci¹,

Song²,

Yun³

et al. 2013

Polish Journal of Veterinary Sciences

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“…Recently, tramadol was reported to be metabolised faster to inactive metabolites in goats (de Sousa et al 2008), dogs (KuKanich and Papich 2004;Giorgi et al 2009a, c), dromedary camels (Elghazali et al 2008), donkeys (Giorgi et al 2009b) and horses (Giorgi et al 2007) than in cats (Pypendop and Ilkiw 2008). Focusing on dogs, several pharmaceutical formulations, administered by different routes, have been tested; I/V (McMillan et al 2008) and extradural (Vettorato et al 2009) injections, oral immediate release (KuKanich and Papich 2004) and sustained release (Giorgi et al 2009c) tablets and rectal suppositories (Giorgi et al 2009a). Despite recent studies have shown the tramadol can be effective either alone (Yazbek and Fantoni 2005) than in combination with other drugs (Monteiro et al 2009), the clinical effectiveness of this drug has been questioned in formulations that mainly allow the drug to be metabolised to inactive substances, suggesting that these routes of administration would not be suitable as an effective and safe treatment for pain in dogs as it is in humans (McMillan et al 2008;Giorgi et al 2009a, c;Vettorato et al 2009).…”

mentioning

confidence: 99%

“…Pharmaceutical formulation seems to be related to both the bioavailability of tramadol and the metabolic patterns leading to different amount of M1. In detail, the administration by the oral route undergoes through gastrointestinal first pass effect; immediate release tablets and sustained release capsules show large divergences in bioavailability of 65% (KuKanich and Papich 2004) and 10% (Giorgi et al 2009c), respectively. Likewise, rectal administration of tramadol suppositories shows very low bioavailability of 10% (Giorgi et al 2009a).…”

mentioning

confidence: 99%

Pharmacokinetic and urine profile of tramadol and its major metabolites following oral immediate release capsules administration in dogs

et al. 2009

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The aim of the present paper was to test the oral administration of oral immediate release capsules of tramadol in dogs, to asses both its pharmacokinetic properties and its urine profile. After capsules administration of tramadol (4 mg/kg), involving eight male Beagle dogs, the concentration of tramadol and its main metabolites, M1, M2 and M5, were determined in plasma and urine using an HPLC method. The plasma concentrations of tramadol and metabolites were fitted on the basis of mono- and non-compartmental models, respectively. Tramadol was detected in plasma from 5 min up to 10 h in lesser amounts than M5 and M2, detected at similar concentrations, while M1 was detected in negligible amounts. In the urine, M5 and M1 showed the highest and smallest amount, respectively; M1 and M5 resulted widely conjugate with glucuronic acid. In conclusion, after oral administration of tramadol immediate release capsules, the absorption of the active ingredient was rapid, but its rapid metabolism quickly transformed the parental drug to high levels of M5 and M2, showing an extensive elimination via the kidney. Hence, in the dog, the oral immediate release pharmaceutical formulation of tramadol would have different pharmacokinetic behaviour than in humans.

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“…Although it has been used for some time now, our understanding and ability to predict the time course of its pharmacological effects in animals are still hampered by the presence of active metabolites and the coexistence of opioid and non-opioid mechanisms. Recently, T has been reported to be metabolized faster to inactive metabolites N-desmethyl tramadol (M2) and O,N-didesmethyl tramadol (M5), in goats (Sousa et al, 2008), dogs (McMillan et al, 2008;Giorgi et al, 2009a;2009b;2009c;2009d;2010a;Kukanich and Papich, 2011), horses (Giorgi et al, 2007;Shilo et al, 2008;Cox et al, 2010;Giorgi et al, 2010b), llamas , alpacas (Giorgi et al, 2010c), peafowl (Black et al, 2010), hawks than in cats (Pypendop and Ilkiw, 2008). The use of T has also been suggested for zoo animals .…”

Section: Tramadolmentioning

confidence: 99%

“…It is possible therefore that this drug may not provide as effective and safe treatment for pain as in humans (Giorgi et al, 2007;2009a;2009b;2009c;2009d;2010a;2010c;Sousa et al, 2008;Kukanich and Papich, 2011). No stereoselective pharmacokinetic studies on T and its metabolite have been reported in animals to date.…”

Section: Tramadolmentioning

confidence: 99%

Tramadol Vs Tapentadol: Anew Horizon in Pain Treatment?

Giorgi¹

2012

American Journal of Animal and Veterinary Sciences

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Problem statement: Acute and chronic pain is a common presenting sign in animal species and human beings. Approach: Classical opioids provide very effective pain relief, although they may be less effective in the treatment of chronic pain due to their limited therapeutic windows and the induced opioid receptor down regulation. Atypical opioids, such as tramadol and tapentadol, have a dual mechanism of action and have been designed to overcome these issues through an opiate-sparing effect. Results: Tramadol activates mu opioid receptors and in addition, inhibits serotonin and noradrenalin reuptake. These actions are the result of the different enantiomers and tend to be reliant on their metabolism. Indeed, the O-desmethyltramadol phase I metabolite, is 200-300 times more potent for mu opioid receptor activation than the parental compound. For these reasons, the drug's effectiveness can vary among subjects. In veterinary medicine its effectiveness, especially after oral administration, is still uncertain and controversial. Tapentadol is a novel, atypical opioid with a unique mechanism of action. It was launched on the European drug market at the end of 2011. It has been proposed as the first representative of a new pharmacological class of centrally acting analgesics, namely, the mu opioid receptor agonist, noradrenalin reuptake inhibitors. The first human studies describe this molecule as safe and effective (equianalgesic to morphine). The drug has great potential for veterinary use because it exists as a single enantiomer only, it does not require metabolic activation to be effective and adverse effects triggered by the serotonin reuptake inhibition action are negligible. Conclusion/Recommendations: For these reasons, TAP is a promising compound however at this stage, more investigation is required before it can be recommended for regular use in veterinary medicine, the possibility of undesirable effects is yet to be entirely excluded.

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Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study

Cited by 49 publications

References 7 publications

Pharmacokinetics and pharmacodynamics (PK/PD) of irbesartan in Beagle dogs after oral administration at two dose rates

Pharmacokinetics and pharmacodynamics (PK/PD) of irbesartan in Beagle dogs after oral administration at two dose rates

Pharmacokinetic and urine profile of tramadol and its major metabolites following oral immediate release capsules administration in dogs

Tramadol Vs Tapentadol: Anew Horizon in Pain Treatment?

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