Pharmacokinetics of Morphine and its Surrogates VII: High-Performance Liquid Chromatographic Analyses and Pharmacokinetics of Methadone and its Derived Metabolites in Dogs

Garrett, Edward R.; Derendorf, Hartmut; Mattha, Amir G.

doi:10.1002/jps.2600741114

Cited by 29 publications

(18 citation statements)

References 18 publications

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“…The pharmacokinetics of codeine in dogs is similar to the pharmacokinetics of other opioids in dogs, including morphine (Barnhart et al, 2000;KuKanich et al, 2005b;KuKanich & Borum, 2008;Henao-Guerrero et al, 2009), hydromorphone (Guedes et al, 2008;KuKanich et al, 2008a), oxymorphone (KuKanich et al, 2008b), methadone (Garrett et al, 1985;KuKanich et al, 2005a), and tramadol (KuKanich & Papich, 2004b;McMillan et al, 2008;Vettorato et al, 2009). The plasma clearance of codeine was rapid, 29.94 mL ⁄ min ⁄ kg, similar to previously reported values of hepatic blood flow in Greyhounds, 25 mL ⁄ min ⁄ min (Mills, 2003).…”

Section: Discussionsupporting

confidence: 83%

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs

KuKanich

2010

Journal of Veterinary Pharmacology and Therapeutics

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The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine-6-glucuronide after IV codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine-6-glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs.Six healthy Greyhound dogs were administered 0.734 mg/kg codeine IV and acetaminophen (10.46 mg/kg mean dose) with codeine (1.43 mg/kg mean dose) orally. Blood samples were obtained at predetermined time points for the determination of codeine, morphine, and codeine-6-glucuronide plasma concentrations by LC/MS and acetaminophen by HPLC with UV detection.Codeine was rapidly eliminated after IV administration (T½ =1.22 hr; clearance=29.94 mL/min/ kg; volume of distribution=3.17 L/kg) with negligible amounts of morphine present, but large amounts of codeine-6-glucuronide (C MAX =735.75 ng/mL) were detected. The oral bioavailability of codeine was 4%, morphine concentrations were negligible, but large amounts of codeine-6-glucuronide (C MAX =1952.86 ng/mL) were detected suggesting substantial first pass metabolism. Acetaminophen was rapidly absorbed (C MAX =6.74 μg/mL; T MAX =0.85 hr) and eliminated (T½=0.96 hr).In conclusion, the pharmacokinetics of codeine were similar to other opioids in dogs with a short half-life, rapid clearance, large volume of distribution, and poor oral bioavailability. High concentrations of codeine-6-glucuronide were detected after IV and oral administration.

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Section: Discussionsupporting

confidence: 83%

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs

KuKanich

2010

Journal of Veterinary Pharmacology and Therapeutics

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“…, 2004). A study in four dogs demonstrated EDDP and EDMP to be minor metabolites and it was hypothesized that CYP3A might not be a major metabolizing enzyme of methadone in dogs (Garrett et al. , 1985).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, methadone is primarily metabolized by CYP3A to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP) and further metabolized to 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EDMP) (Kharasch et al, 2004). A study in four dogs demonstrated EDDP and EDMP to be minor metabolites and it was hypothesized that CYP3A might not be a major metabolizing enzyme of methadone in dogs (Garrett et al, 1985). The results of the current study agree with the hypothesis that CYP3A is not a major metabolizing enzyme in dogs because administration of an inhibitor had no observable effect in five of six dogs.…”

Section: Time (H)mentioning

confidence: 99%

“…Therapeutic blood concentrations of methadone for acute pain have been reported to be between 33 and 59 ng/mL (Gourlay et al, 1982(Gourlay et al, , 1986. The pharmacokinetics and pharmacodynamics of methadone following parenteral administration have been evaluated in dogs (Schlitt et al, 1978;Stanley et al, 1980;Garrett et al, 1985;Schmidt et al, 1994). It showed variable pharmacokinetics, with the elimination half-life ranging from 1.75 to 4 h following i.v.…”

Section: Introductionmentioning

confidence: 99%

“…It showed variable pharmacokinetics, with the elimination half-life ranging from 1.75 to 4 h following i.v. and s.c. administration (Schlitt et al, 1978;Garrett et al, 1985;Schmidt et al, 1994). There are no reports of oral administration of methadone to dogs.…”

Section: Introductionmentioning

confidence: 99%

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The effects of inhibiting cytochrome P450 3A, p‐glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs

KuKanich

Lascelles

Aman

et al. 2005

Vet Pharm & Therapeutics

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Methadone is an opioid, which has a high oral bioavailability (>70%) and a long elimination half-life (>20 h) in human beings. The purpose of this study was to evaluate the effects of ketoconazole [a CYP3A and p-glycoprotein (p-gp) inhibitor] and omeprazole (an H+,K(+)-ATPase proton-pump inhibitor) on oral methadone bioavailability in dogs. Six healthy dogs were used in a crossover design. Methadone was administered i.v. (1 mg/kg), orally (2 mg/kg), again orally following oral ketoconazole (10 mg/kg q12 h for two doses), and following omeprazole (1 mg/kg p.o. q12 h for five doses). Plasma concentrations of methadone were analyzed by high-pressure liquid chromatography or fluorescence polarization immunoassay. The mean +/- SD for the elimination half-life, volume of distribution, and clearance were 1.75 +/- 0.25 h, 3.46 +/- 1.09 L/kg, and 25.14 +/- 9.79 mL/min.kg, respectively following i.v. administration. Methadone was not detected in any sample following oral administration alone or following oral administration with omeprazole. Following administration with ketoconazole, detectable concentrations of methadone were present in one dog with a 29% bioavailability. MDR-1 genotyping, encoding p-gp, was normal in all dogs. In contrast to its pharmacokinetics humans, methadone has a short elimination half-life, rapid clearance, and low oral bioavailability in dogs and the extent of absorption is not affected by inhibition of CYP3A, p-gp, and gastric acid secretion.

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Opioids

Duke‐Novakovski¹

2013

Pain Management in Veterinary Practice

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Pharmacokinetics of Morphine and its Surrogates VII: High-Performance Liquid Chromatographic Analyses and Pharmacokinetics of Methadone and its Derived Metabolites in Dogs

Cited by 29 publications

References 18 publications

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs

The effects of inhibiting cytochrome P450 3A, p‐glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs

Opioids

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