Eichelbaum M, Tomson T, Tybring G, Bertilsson L
Clin Pharmacokinet. 1985 Jan-Feb;10(1):80-90. doi: 10.2165/00003088-198510010-00004.
The metabolism of carbamazepine (CBZ) was studied in 3 groups of subjects: (1) 6 healthy volunteers given a single dose of 200mg carbamazepine; (2) 4 epileptic patients on carbamazepine monotherapy; and (3) 5 patients receiving carbamazepine in combination with other anticonvulsants. Carbamazepine kinetics in the patients were investigated by use of 15N-CBZ. The mean plasma clearances of carbamazepine were 19.8, 54.6 and 113.3 ml/h/kg in groups 1, 2 and 3, respectively. The increased clearance in the patients was mainly due to an induction of the epoxide-diol pathway, as reflected by an increased urinary excretion of the trans-CBZ-diol metabolite. The urinary excretion (as a percentage of the administered dose) of 9-hydroxymethyl-10-carbamoyl-acridan (9-OH-CBZ) was also increased, whereas the excretion of 2-OH-CBZ and 3-OH-CBZ in groups 2 and 3 were decreased in comparison with group 1. As it has been suggested that 9-OH-CBZ is formed from carbamazepine-10,11-epoxide (CBZ-E) or trans-CBZ-diol, the formation of 9-OH-CBZ was investigated in 3 patients with trigeminal neuralgia treated with carbamazepine or CBZ-E as monotherapy on separate occasions. The urinary excretion of 9-OH-CBZ was 1.9, 3.3 and 4.0% of the trans-CBZ-diol excretion during CBZ-E therapy and 23, 32 and 24%, respectively, during carbamazepine administration. Thus only a minor part of the 9-OH-CBZ excreted in urine during carbamazepine therapy is formed via the epoxide-diol pathway. Data on plasma concentrations of carbamazepine and CBZ-E, and on urinary excretion of trans-CBZ-diol from 4 patients on carbamazepine therapy were used to calculate the plasma clearance of CBZ-E. The hydration of CBZ-E during carbamazepine therapy was found to be induced, but to a lesser extent than the epoxidation of carbamazepine. The interrelationship between carbamazepine-epoxidation and oxidative metabolic reactions of some other drugs was also studied in 8 healthy volunteers. Carbamazepine-epoxidation was not correlated to 4-hydroxylation of debrisoquine, oxidation of sparteine, 3- and 4-hydroxylation and demethylation of antipyrine, demethylation of amitriptyline, or total metabolism of theophylline.
在三组受试者中研究了卡马西平（CBZ）的代谢情况：（1）6名健康志愿者，单次服用200mg卡马西平；（2）4名单用卡马西平治疗的癫痫患者；（3）5名同时服用卡马西平和其他抗惊厥药物的患者。通过使用15N-CBZ研究了患者体内的卡马西平动力学。卡马西平的平均血浆清除率在第1、2和3组中分别为19.8、54.6和113.3ml/h/kg。患者清除率的增加主要是由于环氧化物-二醇途径的诱导，这可通过反式-CBZ-二醇代谢物尿排泄增加来反映。9-羟甲基-10-氨基甲酰基吖啶（9-OH-CBZ）的尿排泄（占给药剂量的百分比）也增加，而与第1组相比，第2组和第3组中2-OH-CBZ和3-OH-CBZ的排泄减少。由于有人提出9-OH-CBZ由卡马西平-10,11-环氧化物（CBZ-E）或反式-CBZ-二醇形成，因此在3例分别接受卡马西平或CBZ-E单药治疗的三叉神经痛患者中研究了9-OH-CBZ的形成。在CBZ-E治疗期间，9-OH-CBZ的尿排泄分别为反式-CBZ-二醇排泄的1.9%、3.3%和4.0%，在服用卡马西平期间分别为23%、32%和24%。因此，在卡马西平治疗期间尿中排泄的9-OH-CBZ只有一小部分是通过环氧化物-二醇途径形成的。利用4例接受卡马西平治疗患者的卡马西平和CBZ-E血浆浓度数据以及反式-CBZ-二醇的尿排泄数据来计算CBZ-E的血浆清除率。发现卡马西平治疗期间CBZ-E的水合作用被诱导，但程度低于卡马西平的环氧化作用。还在8名健康志愿者中研究了卡马西平环氧化与其他一些药物氧化代谢反应之间的相互关系。卡马西平环氧化与去甲异喹胍的4-羟化、司巴丁的氧化、安替比林的3-和4-羟化及去甲基化、阿米替林的去甲基化或茶碱的总代谢均无相关性。
