Year: 2011
Type: dissertation
Study design: Clinical Trial
Abstract: Cytochrome P450 (CYP) enzymes are important for the metabolism of many drugs.The inhibition or induction of the CYP enzymes has been found to be a major mechanism behind pharmacokinetic drug-drug interactions.Oxycodone is an opioid analgesic used increasingly in the treatment of moderate and severe pain in inpatient and outpatient care.Since oxycodone is extensively metabolized by CYP2D6 and CYP3A enzymes, it might be prone to drug interactions.In the present studies, the effect of CYP2D6 and CYP3A inhibitors on the pharmacokinetics and pharmacological effects of oxycodone were studied by using a randomized, placebo-controlled crossover study design in clinical trials carried out with healthy volunteers.Although the inhibition of CYP2D6 enzyme by paroxetine considerably decreased the metabolism of oxycodone to oxymorphone, it did not lead to increased concentrations of the parent drug oxycodone.However, the CYP3A inhibition by itraconazole increased the exposure to oxycodone by 1.5-and 2.4-fold after the intravenous and oral administration of oxycodone, respectively.Concomitant treatment with paroxetine and itraconazole increased the exposure to oxycodone by 2.0-and 2.9-fold after the intravenous and oral administration of oxycodone, respectively.A short course of telithromycin increased the exposure to oxycodone by 1.8-fold whereas the use of miconazole oral gel resulted in a 1.6-fold increased exposure to oxycodone.Although these pharmacokinetic interactions clearly increased the achieved plasma concentrations of oxycodone, the used PD models were not able to detect clinically relevant changes in the pharmacological effects of oxycodone after a single low dose to healthy volunteers.The results of these studies demonstrate that the inhibition of CYP2D6 has most likely no clinical relevance for the metabolism of oxycodone, if the function of the CYP3A dependent pathway is normal.On the contrary, the inhibition of CYP3A may lead to clinically relevant increases in oxycodone concentrations.In addition, it was noted that the role of the CYP2D6dependent metabolism of oxycodone is emphasised if the CYP3A4 pathway is inhibited.Although the concomitant use of oxycodone with telithromycin or with miconazole oral gel increased the achieved oxycodone concentrations only moderately, these interactions might have clinical significance in the prolonged use of oxycodone.
Source: UTUPub (University of Turku)
Author: Grönlund, Juha
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2287885812