Effect of telithromycin on the pharmacokinetics and pharmacodynamics of oral oxycodone.
The aim of this study is to determine whether the inhibition of CYP2D6 and CYP3A4 enzyme activity with telithromycin affects the pharmacokinetics and pharmacodynamics of orally administered oxycodone in a randomized 2-phase crossover study. Eleven healthy subjects were pretreated with 800 mg of oral telithromycin or placebo for 4 days. On day 3, they ingested 10 mg of immediate-release oxycodone. Plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 hours, and pharmacodynamic effects were evaluated. Telithromycin increased the area under the plasma concentration-time curve (AUC(0-infinity)) of oxycodone by 80% (P < .001) and reduced the AUC(0-infinity) of noroxycodone by 46% (P < .001). Most of the pharmacokinetic changes were seen in the elimination phase, with little effect by telithromycin on the peak concentration of oxycodone. Pharmacodynamic effects of oxycodone were modestly enhanced by telithromycin. In conclusion, telithromycin clearly reduces the N-demethylation of oxycodone to noroxycodone by inhibiting the CYP450 3A4 enzyme. The use of telithromycin in patients receiving multiple doses of oxycodone for pain relief may increase the risk of opioid adverse effects. Reduction of oxycodone dose by 25% to 50% followed by readjustment according to the clinical response might be appropriate.
Grönlund
Juha
J
Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, Turku, Finland. juha.gronlund@utu.fi
Saari
Teijo
T
Hagelberg
Nora
N
Martikainen
Ilkka K
IK
Neuvonen
Pertti J
PJ
Olkkola
Klaus T
KT
Laine
Kari
K
D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D048628:Ketolides / Q000494:pharmacology*; D008297:Male; D010098:Oxycodone / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017288:Pain Threshold / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects*
D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D048628:Ketolides; D010098:Oxycodone; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C106791:telithromycin