Tornatore K M, Reed K, Walshe J J, Venuto R C
Center for Clinical Pharmacy Research, School of Pharmacy, State University of New York at Buffalo 14260.
Pharmacotherapy. 1994 Jan-Feb;14(1):111-8. doi: 10.1002/j.1875-9114.1994.tb02795.x.
To examine the pharmacodynamic patterns of cortisol and pharmacokinetic values of long-term methylprednisolone in renal transplant recipients.
Twenty-four-hour pharmacokinetic and pharmacodynamic evaluation of patients who participated in a glucocorticoid-monitoring program.
University-based renal transplant clinic.
Fourteen renal transplant recipients studied during a clinically stable period.
The daily oral methylprednisolone dose for each patient was administered intravenously, and serial plasma cortisol and methylprednisolone samples were obtained over 24 hours.
Methylprednisolone was analyzed by high-performance liquid chromatography. The baseline morning cortisol serum concentrations ranged from 9.8-210.7 ng/ml. After the drug was administered, cortisol declined in a linear fashion with a mean suppression half-life of 2.4 +/- 0.9 hours. The cortisol nadir was reached at 12-16 hours in 11 of 14 patients. The return cortisol area under the curve (AUC-Cret) was noted in all patients and ranged from 57-987 ng.hr/ml. The total cortisol area under the curve was greater in patients who had been transplanted for longer than 2 years (1676 +/- 252 vs 836 +/- 405 ng.hr/ml; p < 0.05) compared with more recently transplanted patients. Methylprednisolone clearance ranged from 100-1181 ml/hr/kg with a mean volume of distribution of 1.3 +/- 0.6 L/kg. The methylprednisolone half-life ranged from 1.2-4.7 hours. The correlation between AUC-Cret and methylprednisolone AUC was -0.64 (p < 0.05).
The pharmacodynamic response of cortisol in renal transplant recipients may be associated in part with long-term steroid exposure. However, the interrelationship between the endocrine and immune system may also affect cortisol's disposition and subsequent recovery patterns in this population. Considerable interpatient variability was apparent in both the cortisol pharmacodynamic response as well as the pharmacokinetics of methylprednisolone. These findings suggest a more individualized dosing method may be necessary to optimize the immunosuppressive effect of glucocorticoids and minimize clinical toxicity.
研究肾移植受者中皮质醇的药效学模式及长期甲泼尼龙的药代动力学值。
对参与糖皮质激素监测项目的患者进行24小时药代动力学和药效学评估。
大学附属医院肾移植门诊。
14名在临床稳定期接受研究的肾移植受者。
将每位患者每日口服的甲泼尼龙剂量改为静脉给药，并在24小时内采集系列血浆皮质醇和甲泼尼龙样本。
采用高效液相色谱法分析甲泼尼龙。晨间皮质醇血清基线浓度范围为9.8 - 210.7 ng/ml。给药后，皮质醇呈线性下降，平均抑制半衰期为2.4±0.9小时。14例患者中有11例在12 - 16小时达到皮质醇最低点。所有患者均观察到皮质醇曲线下面积回升值（AUC-Cret），范围为57 - 987 ng.hr/ml。移植时间超过2年的患者皮质醇曲线下总面积更大（1676±252 vs 836±405 ng.hr/ml；p<0.05），与近期移植患者相比。甲泼尼龙清除率范围为100 - 1181 ml/hr/kg，平均分布容积为1.3±0.6 L/kg。甲泼尼龙半衰期范围为1.2 - 4.7小时。AUC-Cret与甲泼尼龙AUC之间的相关性为-0.64（p<0.05）。
肾移植受者中皮质醇的药效学反应可能部分与长期类固醇暴露有关。然而，内分泌系统与免疫系统之间的相互关系也可能影响该人群中皮质醇的处置及后续恢复模式。皮质醇药效学反应以及甲泼尼龙药代动力学在患者间存在明显差异。这些发现表明，可能需要更个体化的给药方法，以优化糖皮质激素的免疫抑制效果并将临床毒性降至最低。
