Bredberg Eva, Andersson Tommy B, Frison Lars, Thuresson Annelie, Johansson Susanne, Eriksson-Lepkowska Maria, Larsson Marita, Eriksson Ulf G
Experimental Medicine, AstraZeneca R&D, Mölndal, Sweden.
Clin Pharmacokinet. 2003;42(8):765-77. doi: 10.2165/00003088-200342080-00005.
Ximelagatran is an oral direct thrombin inhibitor currently in clinical development for the prevention and treatment of thromboembolic disorders. After oral administration, ximelagatran is rapidly absorbed and extensively bioconverted, via two intermediates (ethyl-melagatran and hydroxy-melagatran), to its active form, melagatran. In vitro studies have shown no evidence for involvement of cytochrome P450 (CYP) enzymes in either the bioactivation or the elimination of melagatran.
To investigate the potential of ximelagatran, the intermediates ethyl-melagatran and hydroxy-melagatran, and melagatran to inhibit the CYP system in vitro and in vivo, and the influence of three CYP substrates on the pharmacokinetics of melagatran in vivo.
The CYP inhibitory properties of ximelagatran, the intermediates and melagatran were tested in vitro by two different methods, using heterologously expressed enzymes or human liver microsomes. Diclofenac (CYP2C9), diazepam (CYP2C19) and nifedipine (CYP3A4) were chosen for coadministration with ximelagatran in healthy volunteers. Subjects received oral ximelagatran 24mg and/or diclofenac 50mg, a 10-minute intravenous infusion of diazepam 0.1 mg/kg, or nifedipine 60mg. The plasma pharmacokinetics of melagatran, diclofenac, diazepam, N-desmethyl-diazepam and nifedipine were determined when administered alone and in combination with ximelagatran.
No inhibition, or only minor inhibition, of CYP enzymes by ximelagatran, the intermediates or melagatran was shown in the in vitro studies, suggesting that ximelagatran would not cause CYP-mediated drug-drug interactions in vivo. This result was confirmed in the clinical studies. There were no statistically significant differences in the pharmacokinetics of diclofenac, diazepam and nifedipine on coadministration with ximelagatran. Moreover, there were no statistically significant differences in the pharmacokinetics of melagatran when ximelagatran was administered alone or in combination with diclofenac, diazepam or nifedipine.
As ximelagatran did not exert a significant effect on the hepatic CYP isoenzymes responsible for the metabolism of diclofenac, diazepam and nifedipine, it is reasonable to expect that it would have no effect on the metabolism of other drugs metabolised by these isoenzymes. Furthermore, the pharmacokinetics of melagatran after oral administration of ximelagatran are not expected to be altered by inhibition or induction of CYP2C9, CYP2C19 or CYP3A4. Together, the in vitro and in vivo studies indicate that metabolic drug-drug interactions involving the major human CYP enzymes should not be expected with ximelagatran.
希美加群是一种口服直接凝血酶抑制剂，目前正处于预防和治疗血栓栓塞性疾病的临床研发阶段。口服给药后，希美加群迅速吸收并通过两种中间体（乙基-美拉加群和羟基-美拉加群）广泛生物转化为其活性形式美拉加群。体外研究表明，细胞色素P450（CYP）酶在美拉加群的生物活化或消除过程中均未发挥作用。
研究希美加群、中间体乙基-美拉加群和羟基-美拉加群以及美拉加群在体外和体内抑制CYP系统的可能性，以及三种CYP底物对美拉加群体内药代动力学的影响。
采用两种不同方法在体外测试希美加群、中间体和美拉加群的CYP抑制特性，分别使用异源表达酶或人肝微粒体。选择双氯芬酸（CYP2C9）、地西泮（CYP2C19）和硝苯地平（CYP3A4）与希美加群在健康志愿者中联合给药。受试者口服24mg希美加群和/或50mg双氯芬酸，静脉输注10分钟0.1mg/kg地西泮，或口服60mg硝苯地平。单独给药以及与希美加群联合给药时，测定美拉加群、双氯芬酸、地西泮、N-去甲基-地西泮和硝苯地平的血浆药代动力学。
体外研究表明，希美加群、中间体或美拉加群对CYP酶无抑制作用或仅有轻微抑制作用，提示希美加群在体内不会引起CYP介导的药物相互作用。临床研究证实了这一结果。双氯芬酸、地西泮和硝苯地平与希美加群联合给药时，药代动力学无统计学显著差异。此外，单独给药或与双氯芬酸、地西泮或硝苯地平联合给药时，美拉加群的药代动力学也无统计学显著差异。
由于希美加群对负责双氯芬酸、地西泮和硝苯地平代谢的肝CYP同工酶无显著影响，因此可以合理预期它对这些同工酶代谢的其他药物的代谢也无影响。此外，口服希美加群后美拉加群的药代动力学预计不会因CYP2C9、CYP2C19或CYP3A4的抑制或诱导而改变。总之，体外和体内研究表明，希美加群预计不会与主要的人CYP酶发生代谢性药物相互作用。
