Centrally administered CYP2D inhibitors increase oral tramadol analgesia in rats.
Centrally administered CYP2D inhibitors increase oral tramadol analgesia in rats.
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DOI：
10.1016/j.brainresbull.2020.09.001
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发表时间：
2020-11
影响因子：
3.8
通讯作者：
Tyndale RF
中科院分区：
文献类型：
--
作者：
McMillan DM;El-Sherbeni AA;Richards J;Tyndale RF
细胞色素P450 2D （CYP2D）介导几种精神活性药物的激活和失活，包括阿片类药物，它可以改变药物反应。曲马多是一种合成的阿片类药物，其本身具有镇痛活性，并被CYP2D代谢激活为o -去甲基曲马多（ODMST），一种阿片受体激动剂。我们研究了大鼠口服曲马多后脑CYP2D代谢对中枢曲马多和ODSMT水平的影响，以及由此产生的镇痛反应。在口服曲马多之前，先在脑室内给予CYP2D抑制剂心得安和普罗帕酮，并通过甩尾潜伏期测量镇痛效果。采用LC-ESI-MS/MS微透析法测定血浆和脑组织中曲马多及其代谢物ODSMT和n -去甲基曲马多的药物水平。普帕酮预处理抑制脑CYP2D增加了口服曲马多给药后的镇痛（方差分析p=0.02），镇痛时间曲线下面积增加1.5倍（AUC0-60, p<0.01）。这种作用与脑内曲马多及其代谢物水平的变化有关，与脑内CYP2D抑制一致。综上所述，在口服曲马多剂量预处理下，中心给药CYP2D抑制剂普洛帕酮增加了镇痛（不改变血浆药物或代谢物水平），表明曲马多本身（以及脑内CYP2D的活性）有助于镇痛。
Cytochrome P450 2D (CYP2D) mediates the activation and inactivation of several classes of psychoactive drugs, including opioids, which can alter drug response. Tramadol is a synthetic opioid with analgesic activity of its own as well as being metabolically activated by CYP2D to O-desmethyltramadol (ODMST) an opioid receptor agonist. We investigated the impact of brain CYP2D metabolism on central tramadol and ODSMT levels, and resulting analgesic response after oral tramadol administration in rats. CYP2D inhibitors propranolol and propafenone were administered intracerebroventricularly prior to oral tramadol administration and analgesia was measured by tail-flick latency. Drug levels of tramadol and its metabolites, ODSMT and N-desmethyltramadol, were assessed in plasma and in brain by microdialysis using LC-ESI-MS/MS. Inhibiting brain CYP2D with propafenone pretreatment increased analgesia after oral tramadol administration (ANOVA p=0.02), resulting in a 1.5-fold increase in area under the analgesia-time curve (AUC0–60, p<0.01). This effect was associated with changes in the brain levels of tramadol and its metabolites consistent with brain CYP2D inhibition. In conclusion, under oral tramadol dosing pretreatment with a central administration of the CYP2D inhibitor propafenone increased analgesia (without altering plasma drug or metabolite levels), indicating that tramadol itself (and activity of CYP2D within the brain) contributed to analgesia.
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影响因子：
4.8
作者：
Deuis JR;Dvorakova LS;Vetter I
通讯作者：
Vetter I
影响因子：
6.7
作者：
Laugesen, S;Enggaard, TP;Brosen, K
通讯作者：
Brosen, K
影响因子：
2.9
作者：
Liu, Mingzhou;Wang, Peng;Yue, Jiang
通讯作者：
Yue, Jiang
影响因子：
7.6
作者：
McMillan, Douglas M.;Tyndale, Rachel F.
通讯作者：
Tyndale, Rachel F.
DOI：
10.1111/j.1742-7843.2009.00428.x
发表时间：
2009-09-01
影响因子：
3.1
作者：
Kanaan, Mouna;Daali, Youssef;Desmeules, Jules
通讯作者：
Desmeules, Jules