Bernus I, Dickinson R G, Hooper W D, Eadie M J
Department of Medicine, University of Queensland, Brisbane, Australia.
Epilepsy Res. 1996 Jul;24(3):163-72. doi: 10.1016/0920-1211(96)00011-3.
48-h steady-state metabolic balance studies were carried out in 17 adults receiving long-term anticonvulsant monotherapy. With increasing carbamazepine dosage (1) carbamazepine overall plasma apparent clearance (CL/F), (2) plasma clearance of carbamazepine to urinary carbamazepine-10,11-epoxide, (3) plasma clearance of carbamazepine-10,11-epoxide to urinary unconjugated carbamazepine-10,11-trans-diol and (4) plasma clearances of carbamazepine to urinary 2- and 3-hydroxy carbamazepine all increased. However, with increasing carbamazepine dose there was no increase in the clearance of carbamazepine to (5) its acridan derivative in urine or of (6) the diol, phenolic or acridan metabolites to their metabolically subsequent conjugates excreted in urine. These findings are consistent with ongoing dose-dependent autoinduction of carbamazepine metabolism along the first two stages, but not the final stage, of the epoxide-diol pathway and, to a lesser extent, along pathways yielding phenolic metabolites. However, conjugations of the various plasma phase I metabolites of carbamazepine are not dose-dependent. Plasma concentration ratios of substances involved in consecutive stages of the epoxide-diol pathway, as in previous published studies, suggested apparent dose dependence of the epoxide-->unconjugated diol stage only. Presumably, increased flux along the first two stages of the full epoxide-diol pathway reduces plasma carbamazepine and carbamazepine-10,11-epoxide concentrations largely in parallel, concealing the dose dependence of the conversion of carbamazepine to its epoxide.
对17名接受长期抗惊厥单药治疗的成年人进行了48小时的稳态代谢平衡研究。随着卡马西平剂量增加，（1）卡马西平总体血浆表观清除率（CL/F）、（2）卡马西平向尿中卡马西平-10,11-环氧化物的血浆清除率、（3）卡马西平-10,11-环氧化物向尿中未结合的卡马西平-10,11-反式二醇的血浆清除率以及（4）卡马西平向尿中2-和3-羟基卡马西平的血浆清除率均增加。然而，随着卡马西平剂量增加，卡马西平向（5）其尿中吖啶衍生物的清除率或（6）二醇、酚类或吖啶代谢物向其在尿中排泄的代谢后续结合物的清除率并未增加。这些发现与卡马西平代谢在前两个阶段（而非环氧化物-二醇途径的最后阶段）以及在较小程度上与产生酚类代谢物的途径中持续的剂量依赖性自身诱导一致。然而，卡马西平各种血浆I相代谢物的结合并不依赖于剂量。如先前发表的研究一样，环氧化物-二醇途径连续阶段所涉及物质的血浆浓度比仅表明环氧化物→未结合二醇阶段存在明显的剂量依赖性。据推测，完整环氧化物-二醇途径前两个阶段通量的增加在很大程度上平行降低了血浆卡马西平和卡马西平-10,11-环氧化物的浓度，掩盖了卡马西平向其环氧化物转化的剂量依赖性。
