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 AUC0–60; 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 hepat...
Source: Addiction Biology - Category: Addiction Authors: Tags: Original Article Source Type: research