Villesen H H, Foster D J R, Upton R N, Christrup L L, Somogyi A A, Martinez A, Grant C
Department of Pharmacology and Pharmacotherapy, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark.
Br J Pharmacol. 2006 Nov;149(6):754-60. doi: 10.1038/sj.bjp.0706916. Epub 2006 Oct 3.
At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep.
Five sheep received an intravenous infusion of M6G 2.2 mg kg(-1) over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements.
A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min(-1)) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2.
Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.
目前，关于吗啡的阿片类活性代谢产物吗啡-6-葡萄糖醛酸苷（M6G）在脑-血分配的速率和程度的数据较少。在本研究中，对长期植入监测装置的清醒绵羊进行短期静脉输注后，测定了M6G的脑动力学。
五只绵羊在四分钟内接受了2.2 mg·kg⁻¹的M6G静脉输注。采用基于生理的混合动力学模型进行非线性混合效应分析，根据动脉-矢状窦浓度梯度和脑血流量测量值估算脑动力学。
选择了膜限制模型作为最终模型。M6G的血脑平衡相对较慢（深层隔室达到50%平衡的时间为5.8分钟），从初始隔室（V1，13.7 ml）到小的深层分布容积（V2，18.4 ml）的膜通透性较低（PS，总体均值，2.5 ml·min⁻¹）。初始分布容积存在一定的动物间变异性（%CV，29%），但PS或V2未发现这种情况。
M6G的药代动力学模型显示，脑与血之间的平衡延迟，其性质主要受血脑屏障通透性的限制，这与其理化性质相符。
