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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

Caroline Gadeyne UGent, S Van der Heyden, Frank Gasthuys UGent, Siska Croubels UGent, Stijn Schauvliege UGent and Ingeborgh Polis UGent (2011) JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS. 34(5). p.417-423
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
SUSTAINED-RELEASE, RIFABUTIN DRUG-INTERACTIONS, PLASMA-CONCENTRATIONS, KETOCONAZOLE, INHIBITOR, TRANSPORT, ANTINOCICEPTION, GF120918, RIFAMPIN, SULFATE
journal title
JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS
J. Vet. Pharmacol. Ther.
volume
34
issue
5
pages
417 - 423
Web of Science type
Article
Web of Science id
000295093700001
JCR category
VETERINARY SCIENCES
JCR impact factor
1.181 (2011)
JCR rank
45/141 (2011)
JCR quartile
2 (2011)
ISSN
0140-7783
DOI
10.1111/j.1365-2885.2010.01264.x
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1947818
handle
http://hdl.handle.net/1854/LU-1947818
date created
2011-11-23 13:44:42
date last changed
2011-11-24 16:23:57
@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},
}

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.