酶诱导抗惊厥药对癫痫患者乙琥胺药代动力学的影响。

Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients.

Giaccone M, Bartoli A, Gatti G, Marchiselli R, Pisani F, Latella M A, Perucca E

Clinical Pharmacology Unit, University of Pavia, Italy.

Br J Clin Pharmacol. 1996 Jun;41(6):575-9. doi: 10.1046/j.1365-2125.1996.03601.x.

Abstract

To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500 mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine. 2. Compared with controls, epileptic patients showed markedly shorter ethosuximide half-lives (29.0 +/- 7.8 vs 53.7 +/- 14.3 h, means +/- s.d., P < 0.001) and higher apparent oral clearance (CL/F) values (15.3 +/- 3.8 vs 9.2 +/- 1.9 ml kg-1 h-1, P < 0.001). The apparent volume of distribution (V/F) of ethosuximide was slightly lower in the patients than in controls (0.6 +/- 0.1 vs 0.7 +/- 0.1 l kg-1, P < 0.05). 3. These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity. 4. The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients.

摘要

为评估酶诱导性抗惊厥药物对乙琥胺药代动力学的影响，在12名健康对照受试者和10名接受苯巴比妥、苯妥英和/或卡马西平长期治疗的癫痫患者中，比较了单次口服剂量（500 mg）该药物后血浆乙琥胺浓度。2. 与对照组相比，癫痫患者的乙琥胺半衰期明显缩短（分别为29.0±7.8小时和53.7±14.3小时，均值±标准差，P<0.001），表观口服清除率（CL/F）值更高（分别为15.3±3.8和9.2±1.9 ml·kg-1·h-1，P<0.001）。乙琥胺的表观分布容积（V/F）在患者中略低于对照组（分别为0.6±0.1和0.7±0.1 l·kg-1，P<0.05）。3. 这些发现证明，酶诱导性抗惊厥药物可增加乙琥胺的消除，其作用可能是通过刺激细胞色素CYP3A活性介导的。4. 同时服用酶诱导性抗惊厥药物的患者中乙琥胺清除率的提高可能具有临床相关性。在这些患者中需要更高的乙琥胺剂量才能达到治疗药物浓度。