Perucca Emilio, Johannessen Svein I
Clinical Pharmacology Unit, University of Pavia, Pavia, Italy.
Epileptic Disord. 2003 May;5 Suppl 1:S17-26.
The pharmacokinetic properties of a drug are the primary deter-minant of the extent and duration of drug action, and influence susceptibility to clinically important drug interactions. Most of the older-generation antiepileptic drugs (AEDs) are far from ideal in terms of pharmacokinetics and interaction potential. For example, phenytoin, carbamazepine, and valproic acid exhibit non-linear kinetics; carbamazepine and valproic acid have relatively short half-lives; and most of these drugs cause either enzyme induction (phenytoin, phenobarbital, primidone, carbamazepine) or enzyme inhibition (valproic acid). Compared with older agents, certain new-generation AEDs offer a num-ber of pharmacokinetic advantages, particularly in terms of reduced inter-patient variability in drug clearance and a lower interaction potential. One of the most recently developed of these drugs, levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its half-life is relatively short (6 to 8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice-daily dosing regimen is adequate to produce the desired response.
药物的药代动力学特性是药物作用程度和持续时间的主要决定因素，并影响对具有临床重要意义的药物相互作用的易感性。大多数老一代抗癫痫药物（AEDs）在药代动力学和相互作用潜力方面远非理想。例如，苯妥英、卡马西平和丙戊酸表现出非线性动力学；卡马西平和丙戊酸的半衰期相对较短；并且这些药物中的大多数会引起酶诱导（苯妥英、苯巴比妥、扑米酮、卡马西平）或酶抑制（丙戊酸）。与老一代药物相比，某些新一代AEDs具有许多药代动力学优势，特别是在降低患者间药物清除率的变异性和较低的相互作用潜力方面。这些药物中最新开发的一种，左乙拉西坦，尤其接近满足AED所需的药代动力学特征：（1）它具有高口服生物利用度，不受食物影响；（2）它与血浆蛋白结合不显著；（3）它部分以原形通过肾脏排泄，部分通过水解代谢为无活性的代谢产物，不涉及氧化和结合酶；（4）它具有线性动力学；（5）它不易发生重要的药物相互作用，也不会引起同时给药药物动力学的临床显著改变。虽然它的半衰期相对较短（6至8小时），但其作用持续时间比根据其在血浆中的药代动力学预期的要长，每日两次给药方案足以产生所需的反应。
