Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH) and Department of Pharmacology and Toxicology, University of Toronto, Canada.
Department of Psychiatry, University of Toronto, Canada.
Addict Biol. 2019 Mar;24(2):228-238. doi: 10.1111/adb.12590. Epub 2017 Dec 21.
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.
羟考酮经 CYP2D 代谢为羟吗啡酮。尽管羟吗啡酮是一种更有效的阿片受体激动剂，但由于外周产量低、血脑屏障通透性低和中枢神经系统外排，其对羟考酮镇痛的贡献可能较小。大脑内的 CYP2D 代谢可能导致中枢羟考酮和羟吗啡酮水平的变化，从而影响镇痛。大脑中的 CYP2D 表达和活性受到外源性调节；尼古丁诱导大鼠脑而不是肝 CYP2D，与吸烟者脑中更高的 CYP2D 一致。我们通过用脑室内给予普萘洛尔（基于机制的抑制剂）选择性抑制脑 CYP2D 和用尼古丁诱导脑 CYP2D 来评估大鼠脑 CYP2D 在口服给予羟考酮代谢（体内脑微透析）和镇痛（尾巴闪烁测试）中的作用。抑制脑 CYP2D 增加了羟考酮后的脑羟考酮水平（1.8 倍；P<0.03）和镇痛（AUC 增加 1.5 倍；P<0.001），而诱导脑 CYP2D 增加了脑羟吗啡酮水平（4.6 倍；P<0.001）并降低了镇痛（0.8 倍；P<0.02）。抑制诱导的脑 CYP2D 逆转了羟考酮水平的变化（1.2 倍；P>0.1）和镇痛（1.1 倍；P>0.3）。脑而非血浆的代谢比值受预处理的影响。峰值镇痛与体外脑（P<0.003）而不是肝（P>0.9）CYP2D 活性呈负相关。改变脑 CYP2D 不会影响口服羟吗啡酮的镇痛作用（所有组的 AUC 之间的 P>0.9），羟吗啡酮不是 CYP2D 的底物。因此，脑 CYP2D 代谢改变了局部羟考酮水平和反应，表明 CYP2D 活性增加的人可能对羟考酮的反应降低。改变个体羟考酮反应的因素可能有助于优化治疗并最小化滥用倾向。
