Ragueneau-Majlessi Isabelle, Levy Rene H, Bergen Donna, Garnett William, Rosenfeld William, Mather Gary, Shah Jaymin, Grundy John S
Department of Pharmaceutics, University of Washington, H-272 Health Sciences Building, PO Box 357610, Seattle, WA 98195, USA.
Epilepsy Res. 2004 Nov;62(1):1-11. doi: 10.1016/j.eplepsyres.2004.06.008.
Carbamazepine is metabolized by CYP3A4 and several other cytochrome P450 enzymes. The potential effects of zonisamide on carbamazepine pharmacokinetics (PK) have not been well characterized, with contradictory literature reports. Hence, an in vitro study was designed to evaluate the cytochrome P450 inhibition spectrum of zonisamide using human liver microsomes. Further, an in vivo steady-state study was performed to measure the effect of zonisamide on carbamazepine PK in epileptic patients, and monitor zonisamide PK. In vitro human liver microsomes were incubated with zonisamide (200, 600 or 1000 microM) in the presence of appropriate probe substrates to assess selected cytochrome P450 activities. In vivo, the effect of zonisamide, up to 400 mg/day, on the steady-state PK of carbamazepine and carbamazepine-epoxide (CBZ-E) was studied in 18 epileptic patients. In vitro, zonisamide did not inhibit CYP1A2 and 2D6, and only weakly inhibited CYP2A6, 2C9, 2C19, and 2E1. The estimated Ki for zonisamide inhibition of CYP3A4 was 1076 microM, 12 times higher than typical unbound therapeutic serum zonisamide concentrations. In vivo, no statistically significant differences were observed for mean Cmax, Tmax, and AUC0-12 of total and free carbamazepine and CBZ-E measured before and after zonisamide administration (300-400 mg/day for 14 days). However, CBZ-E renal clearance was significantly (p < 0.05) reduced by zonisamide. The observed mean zonisamide t1/2 (36.3h), relative to approximately 65 h reported in subjects on zonisamide monotherapy, reflects known CYP3A4 induction by carbamazepine. Based on the lack of clinically relevant in vitro and in vivo effects, adjustment of carbamazepine dosing should not be required with concomitant zonisamide administration.
卡马西平由CYP3A4和其他几种细胞色素P450酶代谢。关于唑尼沙胺对卡马西平药代动力学（PK）的潜在影响，文献报道相互矛盾，尚未得到充分阐明。因此，设计了一项体外研究，使用人肝微粒体评估唑尼沙胺的细胞色素P450抑制谱。此外，进行了一项体内稳态研究，以测量唑尼沙胺对癫痫患者卡马西平PK的影响，并监测唑尼沙胺的PK。在适当的探针底物存在下，将体外人肝微粒体与唑尼沙胺（200、600或1000微摩尔）孵育，以评估选定的细胞色素P450活性。在体内，在18例癫痫患者中研究了每日剂量高达400毫克的唑尼沙胺对卡马西平和卡马西平环氧化物（CBZ-E）稳态PK的影响。在体外，唑尼沙胺不抑制CYP1A2和2D6，仅微弱抑制CYP2A6、2C9、2C19和2E1。唑尼沙胺抑制CYP3A4的估计Ki为1076微摩尔，比典型的未结合治疗性血清唑尼沙胺浓度高12倍。在体内，唑尼沙胺给药前后（14天内每日300 - 400毫克）测量的总卡马西平和游离卡马西平以及CBZ-E的平均Cmax、Tmax和AUC0 - 12未观察到统计学显著差异。然而，唑尼沙胺使CBZ-E的肾清除率显著降低（p < 0.05）。观察到的唑尼沙胺平均t1/2（36.3小时），相对于接受唑尼沙胺单药治疗的受试者报告的约65小时，反映了卡马西平对CYP3A4的已知诱导作用。基于缺乏临床相关的体外和体内效应，同时给予唑尼沙胺时无需调整卡马西平的剂量。
