Perucca Emilio
Institute of Neurology IRCCS C. Mondino Foundation, Pavia, and Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
Br J Clin Pharmacol. 2006 Mar;61(3):246-55. doi: 10.1111/j.1365-2125.2005.02529.x.
Some patients with difficult-to-treat epilepsy benefit from combination therapy with two or more antiepileptic drugs (AEDs). Additionally, virtually all epilepsy patients will receive, at some time in their lives, other medications for the management of associated conditions. In these situations, clinically important drug interactions may occur. Carbamazepine, phenytoin, phenobarbital and primidone induce many cytochrome P450 (CYP) and glucuronyl transferase (GT) enzymes, and can reduce drastically the serum concentration of associated drugs which are substrates of the same enzymes. Examples of agents whose serum levels are decreased markedly by enzyme-inducing AEDs, include lamotrigine, tiagabine, several steroidal drugs, cyclosporin A, oral anticoagulants and many cardiovascular, antineoplastic and psychotropic drugs. Valproic acid is not enzyme inducer, but it may cause clinically relevant drug interactions by inhibiting the metabolism of selected substrates, most notably phenobarbital and lamotrigine. Compared with older generation agents, most of the recently developed AEDs are less likely to induce or inhibit the activity of CYP or GT enzymes. However, they may be a target for metabolically mediated drug interactions, and oxcarbazepine, lamotrigine, felbamate and, at high dosages, topiramate may stimulate the metabolism of oral contraceptive steroids. Levetiracetam, gabapentin and pregabalin have not been reported to cause or be a target for clinically relevant pharmacokinetic drug interactions. Pharmacodynamic interactions involving AEDs have not been well characterized, but their understanding is important for a more rational approach to combination therapy. In particular, neurotoxic effects appear to be more likely with coprescription of AEDs sharing the same primary mechanism of action.
一些难治性癫痫患者可从两种或更多种抗癫痫药物（AEDs）的联合治疗中获益。此外，几乎所有癫痫患者在其一生中的某个时候都会接受其他药物来治疗相关病症。在这些情况下，可能会发生具有临床重要性的药物相互作用。卡马西平、苯妥英、苯巴比妥和扑米酮可诱导多种细胞色素P450（CYP）和葡萄糖醛酸转移酶（GT），并可大幅降低作为相同酶底物的相关药物的血清浓度。血清水平因酶诱导性抗癫痫药物而显著降低的药物包括拉莫三嗪、噻加宾、几种甾体类药物、环孢素A、口服抗凝剂以及许多心血管、抗肿瘤和精神药物。丙戊酸不是酶诱导剂，但它可能通过抑制选定底物的代谢而导致具有临床相关性的药物相互作用，最显著的是苯巴比妥和拉莫三嗪。与 older generation agents相比，大多数最近开发的抗癫痫药物诱导或抑制CYP或GT酶活性的可能性较小。然而，它们可能是代谢介导的药物相互作用的靶点，奥卡西平、拉莫三嗪、非氨酯以及高剂量的托吡酯可能会刺激口服避孕药甾体的代谢。左乙拉西坦、加巴喷丁和普瑞巴林尚未被报道会引起或成为具有临床相关性的药代动力学药物相互作用的靶点。涉及抗癫痫药物的药效学相互作用尚未得到充分表征，但对其的了解对于更合理地进行联合治疗很重要。特别是，具有相同主要作用机制的抗癫痫药物联合使用时，神经毒性作用似乎更有可能发生。
