同时对治疗抵抗性双相情感障碍患者的氯胺酮及其三种主要代谢物进行群体药代动力学建模。
Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression.
机构信息
Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
出版信息
Br J Clin Pharmacol. 2012 Aug;74(2):304-14. doi: 10.1111/j.1365-2125.2012.04198.x.
AIM
To construct a population pharmacokinetic (popPK) model for ketamine (Ket), norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine (2S,6S;2R,6R)-HNK) and hydroxyketamine (HK) in patients with treatment-resistant bipolar depression.
METHOD
Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3 in nine patients following a 40 min infusion of (R,S)-Ket (0.5 mg kg⁻¹) and analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)-HNK, (2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK. A compartmental popPK model was constructed that included all quantified analytes, and unknown parameters were estimated with an iterative two-stage algorithm in ADAPT5.
RESULTS
Ket, norKet, DHNK and (2S,6S;2R,6R)-HNK were present during the first 230 min post infusion and significant concentrations (>5 ng ml⁻¹) were observed on day 1. Plasma concentrations of (2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK were below the limit of quantification. The average (S) : (R) plasma concentrations for Ket and DHNK were <1.0 while no significant enantioselectivity was observed for norKet. There were large inter-patient variations in terminal half-lives and relative metabolite concentrations; at 230 min (R,S)-DHNK was the major metabolite in four out of nine patients, (R,S)-norKet in three out of nine patients and (2S,6S;2R,6R)-HNK in two out of nine patients. The final PK model included three compartments for (R,S)-Ket, two compartments for (R,S)-norKet and single compartments for DHNK and HNK. All PK profiles were well described, and parameters for (R,S)-Ket and (R,S)-norKet were in agreement with prior estimates.
CONCLUSION
This represents the first PK analysis of (2S,6S;2R,6R)-HNK and (R,S)-DHNK. The results demonstrate that while norKet is the initial metabolite, it is not the main metabolite suggesting that future Ket studies should include the analysis of the major metabolites.
目的
构建治疗抵抗性双相情感障碍患者中氯胺酮（Ket）、去甲氯胺酮（norKet）、去氢去甲氯胺酮（DHNK）、羟基氯胺酮（(2S,6S;2R,6R)-HNK）和羟基酮（HK）的群体药代动力学（popPK）模型。
方法
在 9 名患者中，以 0.5mg/kg 的速度输注（R,S）-Ket 40 分钟后，在第 1、2 和 3 天的 40、80、110 和 230 分钟采集血浆样本，并对 Ket、norKet 和 DHNK 对映异构体以及（2S,6S;2R,6R）-HNK、（2S,6S;2R,6R）-HK 和（2S,6R;2R,6S）-HK 进行分析。建立了一个包含所有定量分析物的房室 popPK 模型，并使用 ADAPT5 中的迭代两阶段算法估计未知参数。
结果
在输注后 230 分钟内存在 Ket、norKet、DHNK 和（2S,6S;2R,6R）-HNK，并且在第 1 天观察到显著浓度（>5ng/ml）。（2S,6S;2R,6R）-HK 和（2S,6R;2R,6S）-HK 的浓度低于定量下限。Ket 和 DHNK 的（S）：（R）血浆浓度平均值<1.0，而 norKet 没有明显的对映选择性。终末半衰期和相对代谢物浓度的个体间差异较大；在 230 分钟时，（R,S）-DHNK 是 9 名患者中的 4 名、（R,S）-norKet 是 9 名患者中的 3 名和（2S,6S;2R,6R）-HNK 是 9 名患者中的 2 名的主要代谢物。最终 PK 模型包括（R,S）-Ket 的三个隔室、（R,S）-norKet 的两个隔室和 DHNK 和 HNK 的单个隔室。所有 PK 谱均得到很好的描述，（R,S）-Ket 和（R,S）-norKet 的参数与先前的估计一致。
结论
这是首次对（2S,6S;2R,6R）-HNK 和（R,S）-DHNK 的 PK 分析。结果表明，虽然 norKet 是初始代谢物，但它不是主要代谢物，这表明未来的 Ket 研究应包括主要代谢物的分析。
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