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The influence of modulation of P-glycoprotein and/or cytochrome P450 3A on the pharmacokinetics and pharmacodynamics of orally administered morphine in dogs

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Abstract
The influence of pretreatment with ketoconazole [cytochrome P450 3A (CYP3A) + P-glycoprotein (P-gp) inhibitor], elacridar (selective P-gp inhibitor) and rifampicin (CYP3A + P-gp inducer) on oral morphine pharmacokinetics and pharmacodynamics was investigated in experimental dogs. Seven beagles were used in a four-way crossover design. Morphine hydrochloride was administered orally (2.5 mg/kg) alone (control group CON) or after pretreatment with ketoconazole (group KETO), elacridar (group ELA) or rifampicin (group RIF). Morphine plasma concentrations were analysed by liquid chromatography-tandem mass spectrometry. Sedation scores (none, mild, moderate or severe) were evaluated subjectively. Dogs were significantly (P < 0.05) more sedated after ketoconazole pretreatment. There were no significant differences between group CON and the other pretreatment groups in pharmacokinetic parameters taking both sexes into account. Sex differences were apparent in some pharmacokinetic parameters of morphine. The area under the plasma concentration time curve (AUC(0-infinity)) was significantly higher, and the total body clearance was significantly lower in male compared to female dogs in all treatment groups. Ketoconazole, rifampicin and elacridar pretreatment had no significant effects on morphine pharmacokinetics, although dogs in the ketoconazole group showed higher sedation scores.
Keywords
SUSTAINED-RELEASE, RIFABUTIN DRUG-INTERACTIONS, PLASMA-CONCENTRATIONS, KETOCONAZOLE, INHIBITOR, TRANSPORT, ANTINOCICEPTION, GF120918, RIFAMPIN, SULFATE

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Chicago
Gadeyne, Caroline, S Van der Heyden, Frank Gasthuys, Siska Croubels, Stijn Schauvliege, and Ingeborgh Polis. 2011. “The Influence of Modulation of P-glycoprotein And/or Cytochrome P450 3A on the Pharmacokinetics and Pharmacodynamics of Orally Administered Morphine in Dogs.” Journal of Veterinary Pharmacology and Therapeutics 34 (5): 417–423.
APA
Gadeyne, C., Van der Heyden, S., Gasthuys, F., Croubels, S., Schauvliege, S., & Polis, I. (2011). The influence of modulation of P-glycoprotein and/or cytochrome P450 3A on the pharmacokinetics and pharmacodynamics of orally administered morphine in dogs. JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS, 34(5), 417–423.
Vancouver
1.
Gadeyne C, Van der Heyden S, Gasthuys F, Croubels S, Schauvliege S, Polis I. The influence of modulation of P-glycoprotein and/or cytochrome P450 3A on the pharmacokinetics and pharmacodynamics of orally administered morphine in dogs. JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS. 2011;34(5):417–23.
MLA
Gadeyne, Caroline, S Van der Heyden, Frank Gasthuys, et al. “The Influence of Modulation of P-glycoprotein And/or Cytochrome P450 3A on the Pharmacokinetics and Pharmacodynamics of Orally Administered Morphine in Dogs.” JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS 34.5 (2011): 417–423. Print.
@article{1947818,
  abstract     = {The influence of pretreatment with ketoconazole [cytochrome P450 3A (CYP3A) + P-glycoprotein (P-gp) inhibitor], elacridar (selective P-gp inhibitor) and rifampicin (CYP3A + P-gp inducer) on oral morphine pharmacokinetics and pharmacodynamics was investigated in experimental dogs. Seven beagles were used in a four-way crossover design. Morphine hydrochloride was administered orally (2.5 mg/kg) alone (control group CON) or after pretreatment with ketoconazole (group KETO), elacridar (group ELA) or rifampicin (group RIF). Morphine plasma concentrations were analysed by liquid chromatography-tandem mass spectrometry. Sedation scores (none, mild, moderate or severe) were evaluated subjectively. Dogs were significantly (P {\textlangle} 0.05) more sedated after ketoconazole pretreatment. There were no significant differences between group CON and the other pretreatment groups in pharmacokinetic parameters taking both sexes into account. Sex differences were apparent in some pharmacokinetic parameters of morphine. The area under the plasma concentration time curve (AUC(0-infinity)) was significantly higher, and the total body clearance was significantly lower in male compared to female dogs in all treatment groups. Ketoconazole, rifampicin and elacridar pretreatment had no significant effects on morphine pharmacokinetics, although dogs in the ketoconazole group showed higher sedation scores.},
  author       = {Gadeyne, Caroline and Van der Heyden, S and Gasthuys, Frank and Croubels, Siska and Schauvliege, Stijn and Polis, Ingeborgh},
  issn         = {0140-7783},
  journal      = {JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS},
  keyword      = {SUSTAINED-RELEASE,RIFABUTIN DRUG-INTERACTIONS,PLASMA-CONCENTRATIONS,KETOCONAZOLE,INHIBITOR,TRANSPORT,ANTINOCICEPTION,GF120918,RIFAMPIN,SULFATE},
  language     = {eng},
  number       = {5},
  pages        = {417--423},
  title        = {The influence of modulation of P-glycoprotein and/or cytochrome P450 3A on the pharmacokinetics and pharmacodynamics of orally administered morphine in dogs},
  url          = {http://dx.doi.org/10.1111/j.1365-2885.2010.01264.x},
  volume       = {34},
  year         = {2011},
}

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