心脏手术患者术后疼痛治疗期间吗啡及其 6-葡萄糖醛酸代谢物的药代动力学。

Department of Anesthesiology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Krankenhausstrasse 12, 91054, Erlangen, Germany.

Eur J Drug Metab Pharmacokinet. 2021 Mar;46(2):249-263. doi: 10.1007/s13318-020-00663-z. Epub 2021 Feb 5.

BACKGROUND AND OBJECTIVE

Morphine is a standard analgesic drug for postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide (M6G) in cardiac surgery patients during postoperative analgesia.

METHODS

Twenty-five adult patients undergoing cardiac surgery received postoperative pain therapy by patient-controlled analgesia with intravenous bolus doses of morphine. Plasma concentrations of morphine and M6G were determined from arterial samples. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling.

RESULTS

Data from twenty-one patients (aged 44-79 years) were analyzed. Pharmacokinetics were best described by a three-compartment model for morphine and a two-compartment model for M6G, linked by a transit compartment. Mean (±SD) population estimates for morphine were: clearance (CL) = 1.35±0.40 L/min, central volume of distribution (V) = 8.1±2.2 L, steady-state volume of distribution (V) = 207±83 L, terminal elimination half-life (T) = 177±50 min. Clearance of morphine was proportional to cardiac output. Mean (±SD) population estimates for M6G were: CL = 0.098±0.037 L/min, V = 5.5±0.8 L, V = 15.8±0.8 L, T = 227±74 min. The time to peak concentration of M6G after a bolus dose of morphine was 53±20 min. Clearance of M6G was proportional to estimated glomerular filtration rate.

CONCLUSIONS

The pharmacokinetics of morphine and M6G in pain therapy of cardiac surgery patients could be well described by standard compartmental models. Cardiac output was identified as a significant covariate for morphine clearance, whereas renal function was identified as the most significant covariate for clearance of M6G. These effects should be particularly considered if morphine is administered as a continuous infusion. The developed pharmacokinetic model also enables patient-controlled target-controlled infusion for pain therapy with morphine.

TRIAL REGISTRATION

Clinical Trials NCT02483221 (June 26, 2015).

背景与目的

吗啡是术后疼痛治疗的标准镇痛药物。本研究旨在评估心脏手术患者术后镇痛中吗啡及其活性代谢物吗啡-6-葡萄糖醛酸（M6G）的药代动力学。

方法

25 例接受心脏手术的成年患者接受静脉推注吗啡患者自控镇痛。从动脉样本中测定吗啡和 M6G 的血浆浓度。使用非线性混合效应模型估算群体药代动力学参数。

结果

对 21 例（年龄 44-79 岁）患者的数据进行了分析。吗啡的药代动力学最好通过三房室模型描述，M6G 的药代动力学最好通过两房室模型描述，两者通过转运室连接。吗啡的群体平均（±SD）估算值为：清除率（CL）=1.35±0.40 L/min，中央分布容积（V）=8.1±2.2 L，稳态分布容积（V）=207±83 L，终末消除半衰期（T）=177±50 min。吗啡的清除率与心输出量成正比。M6G 的群体平均（±SD）估算值为：CL=0.098±0.037 L/min，V=5.5±0.8 L，V=15.8±0.8 L，T=227±74 min。静脉推注吗啡后 M6G 的达峰时间为 53±20 min。M6G 的清除率与估计肾小球滤过率成正比。