Levy R H, Schmidt D
Epilepsia. 1985 May-Jun;26(3):199-205. doi: 10.1111/j.1528-1157.1985.tb05406.x.
Criteria that were developed for monitoring free (unbound) rather than total (free plus bound) concentrations of antiepileptic drugs include extensive and variable binding to plasma proteins. Phenytoin and valproic acid belong to this category. It is shown that free drug concentration is independent of total drug concentration, whereas total drug concentration depends on free concentration and free fraction. Because antiepileptic drugs are predominantly bound to albumin, free fraction will increase in the presence of hypoalbuminemia (hepatic and renal disease, burns, and pregnancy). Free fraction also increases because of saturable binding (valproic acid) and competitive binding (valproic acid displacing phenytoin). There is suggestive evidence that side effects may be more closely related to the free, rather than to the total, plasma concentration of phenytoin. The clinical evidence that side effects or therapeutic effects are better correlated to the free, rather than the total, concentration of valproic acid or carbamazepine is not yet convincing. Knowledge of the free concentration improves our understanding of therapeutic and toxic effects of low total plasma concentrations. Further clinical trials are necessary for definitive assessment of the clinical relevance for free drug monitoring of valproic acid, carbamazepine, and phenytoin in the management of epileptic patients.
为监测抗癫痫药物的游离（未结合）浓度而非总（游离加结合）浓度所制定的标准，包括与血浆蛋白的广泛且可变的结合。苯妥英和丙戊酸属于这一类别。研究表明，游离药物浓度独立于总药物浓度，而总药物浓度则取决于游离浓度和游离分数。由于抗癫痫药物主要与白蛋白结合，在低白蛋白血症（肝脏和肾脏疾病、烧伤及妊娠）情况下游离分数会增加。游离分数还会因饱和性结合（丙戊酸）和竞争性结合（丙戊酸置换苯妥英）而增加。有提示性证据表明，苯妥英的副作用可能与游离血浆浓度而非总血浆浓度更密切相关。关于丙戊酸或卡马西平的副作用或治疗效果与游离浓度而非总浓度的相关性更好的临床证据尚不令人信服。了解游离浓度有助于我们更好地理解低总血浆浓度时的治疗和毒性作用。对于在癫痫患者管理中丙戊酸、卡马西平和苯妥英游离药物监测的临床相关性进行明确评估，还需要进一步的临床试验。
