Fattore Cinzia, Messina Sara, Battino Dina, Croci Danilo, Mamoli Daniela, Perucca Emilio
Clinical Pharmacology Unit, University of Pavia, Piazza Botta 10, Pavia, Italy.
Epilepsy Res. 2006 Aug;70(2-3):153-60. doi: 10.1016/j.eplepsyres.2006.04.002. Epub 2006 May 30.
To evaluate the influence of aging on the pharmacokinetics of valproic acid (VPA) at steady-state and on the susceptibility of VPA metabolism to enzyme induction by antiepileptic comedication.
The database of the therapeutic drug monitoring service of a large neurological hospital was searched to identify patients aged > or = 65 years stabilized on VPA therapy. Apparent VPA oral clearance (CL/F) calculated for each elderly patient was compared with that determined in an equal number of VPA-treated controls aged 20-50 years and matched for gender, body weight and antiepileptic drug (AED) comedication.
A total of 71 elderly patients aged 70.0+/-4.4 years, including 20 receiving enzyme inducing AEDs, was included in the main evaluation. In the absence of enzyme inducing comedication, VPA CL/F in the elderly was similar to that found in non-elderly controls (9.7+/-4.6 versus 10.2+/-4.6mlh(-1)kg(-1)). Elderly patients on enzyme inducing comedication, on the other hand, had lower CL/F values than enzyme induced younger controls (11.7+/-5.4 versus 16.0+/-6.3mlh(-1)kg(-1), p<0.05). Since VPA CL/F is known to increase with increasing dosage, a lower VPA dosage in elderly patients comedicated with enzyme inducers compared with controls may have contributed to differences in CL/F between the two groups.
In the absence of enzyme inducing comedication, VPA clearance in the elderly was comparable to that observed in controls. VPA clearance in elderly patients receiving enzyme inducing AEDs was lower than in controls, the difference being probably due to an influence of age as well as to the fact that mean VPA dosage was lower in these patients than in controls. Since our measurements of clearance were based on total serum VPA concentrations and VPA binding to plasma proteins is known to be reduced in old age, it is likely that the clearance of unbound, pharmacologically active, VPA was decreased to an important extent in the elderly, presumably as a result of a decline in drug metabolizing capacity.
评估衰老对丙戊酸（VPA）稳态药代动力学的影响，以及VPA代谢对抗癫痫联合用药酶诱导的易感性。
检索一家大型神经科医院治疗药物监测服务数据库，以确定年龄≥65岁且VPA治疗稳定的患者。计算每位老年患者的VPA表观口服清除率（CL/F），并与同等数量年龄在20 - 50岁、性别、体重和抗癫痫药物（AED）联合用药相匹配的VPA治疗对照者的CL/F进行比较。
主要评估纳入了71名年龄为70.0±4.4岁的老年患者，其中20名接受酶诱导性AEDs治疗。在未使用酶诱导联合用药的情况下，老年患者的VPA CL/F与非老年对照者相似（9.7±4.6对10.2±4.6ml·h⁻¹·kg⁻¹）。另一方面，接受酶诱导联合用药的老年患者的CL/F值低于酶诱导的年轻对照者（11.7±5.4对16.0±6.3ml·h⁻¹·kg⁻¹，p<0.05）。由于已知VPA CL/F随剂量增加而升高，与对照者相比，接受酶诱导剂联合用药的老年患者VPA剂量较低可能导致了两组之间CL/F的差异。
在未使用酶诱导联合用药的情况下，老年患者的VPA清除率与对照者相当。接受酶诱导性AEDs治疗的老年患者的VPA清除率低于对照者，差异可能是由于年龄影响以及这些患者的平均VPA剂量低于对照者。由于我们的清除率测量基于总血清VPA浓度，且已知老年时VPA与血浆蛋白的结合减少，很可能老年时未结合的、具有药理活性的VPA清除率在很大程度上降低，推测是药物代谢能力下降的结果。
