The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone

Abstract

Background and purpose:There is high interindividual variability in the activity of drug-metabolizing enzymes catalysing the oxidation of oxycodone [cytochrome P450 (CYP) 2D6 and 3A], due to genetic polymorphisms and/or drug-drug interactions. The effects of CYP2D6 and/or CYP3A activity modulation on the pharmacokinetics of oxycodone remains poorly explored. Experimental approach: A randomized crossover double-blind placebo-controlled study was performed with 10 healthy volunteers genotyped for CYP2D6 [six extensive (EM), two deficient (PM/IM) and two ultrarapid metabolizers (UM)]. The volunteers randomly received on five different occasions: oxycodone 0.2 mg·kg -1 and placebo; oxycodone and quinidine (CYP2D6 inhibitor); oxycodone and ketoconazole (CYP3A inhibitor); oxycodone and quinidine+ketoconazole; placebo. Blood samples for plasma concentrations of oxycodone and metabolites (oxymorphone, noroxycodone and noroxymorphone) were collected for 24 h after dosing. Phenotyping for CYP2D6 (with dextromethorphan) and CYP3A (with midazolam) were assessed at each session. Key results: CYP2D6 activity was correlated with oxymorphone and noroxymorphone AUCs and Cmax (-0.71 < Spearman correlation coefficient rs < -0.92). Oxymorphone Cmax was 62% and 75% lower in PM than EM and UM. Noroxymorphone Cmax reduction was even more pronounced (90%). In UM, oxymorphone and noroxymorphone concentrations increased whereas noroxycodone exposure was halved. Blocking CYP2D6 (with quinidine) reduced oxymorphone and noroxymorphone Cmax by 40% and 80%, and increased noroxycodone AUC• by 70%. Blocking CYP3A4 (with ketoconazole) tripled oxymorphone AUC• and reduced noroxycodone and noroxymorphone AUCs by 80%. Shunting to CYP2D6 pathway was observed after CYP3A4 inhibition. Conclusions and implications: Drug-drug interactions via CYP2D6 and CYP3A affected oxycodone pharmacokinetics and its magnitude depended on CYP2D6 genotype.

Study of pharmacokinetic interaction of paroxetine and roxithromycin on bencycloquidium bromide in healthy subjects

“…This was confirmed by the absence of significant difference in the C max between the two periods. Moreover, a shunt of a CYP2D6 substrate to metabolism via secondary weekly metabolic pathways such as CYP3A5, when CYP2D6 was deficient, was described in previous studies (Samer et al, 2010;Heiskanen et al, 1998). Thus, the metabolism of BCQB by other enzymes such as CYP3A4/5 and CYP2C19 could also lessen the exposure of BCQB after inhibition of CYP2D6 by paroxetine.…”

Prediction of Drug Response and Safety in Clinical Practice

“…When one isoform is not available (due to inhibition, downregulation, or nonexpression) drugs may be shunted through alternative CYP enzymes resulting in alternative metabolites with varying affinity for the target receptor. Samer et al elegantly demonstrated this phenomenon by inhibiting CYP 3A4 and showing that oxycodone is then metabolized by CYP2D6 to a more potent metabolite [18]. Thus, characterization of the full spectrum of CYP metabolic capacity and understanding of the drug affinities for specific enzymes are necessary to predict the metabolite profile in an individual patient.…”

Analgesic and Anti–Inflammatory Effects of Oxycodone with Adjuvant Drugs in an Experimental Study of Nociceptive and Neuropathic Pain

“…OXY displays analgesia through µ-and probably also κ-opioid receptors [50] and activation of GABA B receptors [51]. OXY is metabolized through the P-450 system, predominantly CYP3A4 to inactive noroxycodone, and to a less extent via CYP2D6 to oxymorphone that displays analgesic effect [52]. Morphine acts exclusively via activation of predominantly μ-opioid receptors and mostly undergoes glucuronidation; it is metabolized through CYP2D6 to a less extent [53].…”