Rat brain CYP2D activity alters in vivo central oxycodone metabolism, levels and resulting analgesia

Abstract

Oxycodone is metabolized by CYP2D to oxymorphone. Despite oxymorphone being a more potent opioid-receptor agonist, its contribution to oxycodone analgesia may be minor because of low peripheral production, low blood-brain barrier permeability and central nervous system efflux. CYP2D metabolism within the brain may contribute to variation in central oxycodone and oxymorphone levels, thereby affecting analgesia. Brain CYP2D expression and activity are subject to exogenous regulation; nicotine induces rat brain, but not liver, CYP2D consistent with higher brain CYP2D in smokers. We assessed the role of rat brain CYP2D in orally administered oxycodone metabolism (in vivo brain microdialysis) and analgesia (tail-flick test) by inhibiting brain CYP2D selectively with intracerebroventricular propranolol (mechanism-based inhibitor) and inducing brain CYP2D with nicotine. Inhibiting brain CYP2D increased brain oxycodone levels (1.8-fold; P < 0.03) and analgesia (1.5-fold AUC ; P < 0.001) after oxycodone, while inducing brain CYP2D increased brain oxymorphone levels (4.6-fold; P < 0.001) and decreased analgesia (0.8-fold; P < 0.02). Inhibiting the induced brain CYP2D reversed the change in oxycodone levels (1.2-fold; P > 0.1) and analgesia (1.1-fold; P > 0.3). Brain, but not plasma, metabolic ratios were affected by pre-treatments. Peak analgesia was inversely correlated with ex vivo brain (P < 0.003), but not hepatic (P > 0.9), CYP2D activity. Altering brain CYP2D did not affect analgesia from oral oxymorphone (P > 0.9 for AUC across all groups), which is not a CYP2D substrate. Thus, brain CYP2D metabolism alters local oxycodone levels and response, suggesting that people with increased brain CYP2D activity may have reduced oxycodone response. Factors that alter individual oxycodone response may be useful for optimizing treatment and minimizing abuse liability.

Cytochrome P450 expression and regulation in the brain

“…CYP2D6 exhibits a broad spectrum of substrate specificity proven by in vitro biochemical assays and showing abilities to metabolize 75 drugs, including antidepressants and neuroleptics (Nebert and Russell 2002). Brain CYP2D takes part in the local metabolism and analgesic effects of codeine (Zhou et al 2013;Tyndale 2015, 2017), oxycodone (McMillan et al 2019), and tramadol (Wang et al 2015). On the other hand, changes in the activity of brain CYP2D and consequent alterations in metabolism of the antipsychotic drug haloperidol diversely affect acute and chronic sideeffects of this drug measured in the rat behavioral models (Miksys et al 2017).…”

Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone

“…After intrathecal administration, the analgesic efficacy of oxymorphone is 40-fold higher and the intrathecal oxymorphone dose for 50% maximum potential effect (MPE) is significantly lower at 0.63 μg/kg, compared with oxycodone at 20 μg/kg [46]. Interestingly, inhibition of CYP2D6 with intracerebroventricular propranolol increases brain oxycodone concentrations and analgesia, whereas induction of CYP2D6 with nicotine increases brain oxymorphone concentrations but decreases analgesia [47]. Further studies may more precisely elucidate the role of brain CYPs on the PK and PD of oxycodone and its metabolites.…”

Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances

“…Furthermore, the elevation of brain CYP2D increased the rate of codeine tolerance (McMillan and Tyndale, 2017). Brain CYP2Dmediated transformation from some other opioids (tramadol and oxycodone) to their metabolites (O-desmethyltramadol and oxymorphone) also affects their analgesia (Wang et al, 2015;McMillan et al, 2019McMillan et al, , 2020. It is worth noting that characteristics of drug-drug interactions in brain are different from liver.…”