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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
Author(s) -
GADEYNE C.,
VAN der HEYDEN S.,
GASTHUYS F.,
CROUBELS S.,
SCHAUVLIEGE S.,
POLIS I.
Publication year - 2011
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/j.1365-2885.2010.01264.x
Subject(s) - ketoconazole , pharmacokinetics , cyp3a , pharmacology , morphine , pharmacodynamics , midazolam , rifampicin , medicine , sedation , chemistry , cytochrome p450 , metabolism , antifungal , tuberculosis , dermatology , pathology
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. J. vet. Pharmacol. Therap. 34 , 417–423. 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–∞ ) 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.