S(+)-ketamine Effect on Experimental Pain and Cardiac Output A Population Pharmacokinetic-Pharmacodynamic Modeling Study in Healthy Volunteers
S(+)-ketamine Effect on Experimental Pain and Cardiac Output A Population Pharmacokinetic-Pharmacodynamic Modeling Study in Healthy Volunteers
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DOI：
10.1097/aln.0b013e3181b437b1
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发表时间：
2009-10-01
期刊：
影响因子：
8.8
通讯作者：
Olofsen, Erik
中科院分区：
文献类型：
--
作者：
Sigtermans, Marnix;Dahan, Albert;Olofsen, Erik
背景：小剂量氯胺酮可作为一种镇痛药用于治疗急性和慢性疼痛。为了进一步了解氯胺酮的治疗效果，作者在健康志愿者中进行了S(+)-氯胺酮镇痛和非镇痛作用的人群药代动力学分析。10名男性和10名女性接受2小时S（+）氯胺酮输注。以每15 min 40 ng/ml的速度增加，最大可达320 ng/ml。测定动脉血浆S(+)-氯胺酮和S（+）去甲氯胺酮浓度、热痛强度、电痛耐受性、药物浓度和心输出量。采用S(+)-氯胺酮浓度与效果、S(+)-氯胺酮+ S(+)-诺氯胺酮浓度与效果的sigmoid Emax模型对数据进行建模。观察到的性别差异仅限于药代动力学模型参数，女性S(+)-氯胺酮和S(+)-诺氯胺酮的清除清除率高出20%，导致男性的药物血浆浓度较高。S（+）氯胺酮在热痛实验中产生的强效镇痛作用是电痛实验的6倍。氯胺酮输注后，镇痛迅速消失；在热痛试验中，而不是电痛试验中，镇痛后是一段时间的痛觉过敏。在测试的剂量范围内，氯胺酮使心输出量增加40-50%。S(+)-诺氯胺酮对所有结局参数的总体效果均未检测到显著一致的贡献。S(+)-氯胺酮的药代动力学表现出临床相关的性别差异。在血浆浓度已经很低的情况下，它是一种有效的镇痛药，但它与强烈的副作用有关。
Background: Low-dose ketamine behaves as an analgesic in the treatment of acute and chronic pain. To further understand ketamine's therapeutic profile, the authors performed a population pharmacokinetic-pharmacodynamic analysis of the S(+)-ketamine analgesic and nonanalgesic effects in healthy volunteers.Methods. Ten men and ten women received a 2-h S(+)ketamine infusion. The infusion was increased at 40 ng/ml per 15 min to reach a maximum of 320 ng/ml. The following measurements were made: arterial plasma S(+)-ketamine and S(+)norketamine concentrations, heat pain intensity, electrical pain tolerance, drug high, and cardiac output. The data were modeled by using sigmoid Emax models of S(+)-ketamine concentration versus effect and S(+)-ketamine + S(+)-norketamine concentrations versus effect.Results. Sex differences observed were restricted to pharmacokinetic model parameters, with a 20% greater elimination clearance of S(+)-ketamine and S(+)-norketamine in women resulting In higher drug plasma concentrations in men. S(+)ketamine produced profound drug high and analgesia with six times greater potency in the heat pain than the electrical pain test. After ketamine-infusion, analgesia rapidly dissipated; in the heat pain test but not the electrical pain test, analgesia was followed by a period of hyperalgesia. over the dose range tested, ketamine produced a 40-50% increase in cardiac output. A significant consistent contribution of S(+)-norketamine to overall effect was detected for none of the outcome parameters.Conclusions. S(+)-ketamine displays clinically relevant sex differences in Its pharmacokinetics. It is a potent analgesic at already low plasma concentrations, but it is associated with intense side effects.