Effects of CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status.. K Kosuge; Y Jun; H Watanabe; M Kimura; M Nishimoto; T Ishizaki; K Ohashi (2001) Drug metabolism and disposition: the biological fate of chemicals display abstract
Diazepam is metabolized by CYP2C19 and CYP3A4 in the liver. CYP2C19 shows genetic polymorphism associated with the poor metabolizer (PM) and extensive metabolizer (EM) phenotypes. The aim of this study was to assess the effect of diltiazem, a CYP3A4 inhibitor, on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status. Thirteen healthy volunteers (eight EMs and five PMs) were given placebo or diltiazem (200 mg) orally for 3 days before and for 7 days after the oral 2-mg dose of diazepam in a double-blind, randomized, crossover manner. The pharmacokinetics and pharmacodynamics of diazepam were assessed with and without diltiazem. Plasma concentrations and area under the plasma concentration-time curves (AUCs) of diazepam and N-desmethyldiazepam were significantly greater in the PM compared with the EM group during the placebo phase. Diltiazem significantly increased AUC and prolonged elimination t(1/2) of diazepam in both the PM and EM groups. These pharmacokinetic changes, however, caused no significant difference in the pharmacodynamics between the two trial phases. Diltiazem affects the pharmacokinetics of diazepam in the PM and EM groups of CYP2C19. Inhibition of CYP3A4 by a concomitant substrate drug like diltiazem may cause a pharmacokinetic interaction with diazepam irrespective of CYP2C19 genotype status, but whether this interaction would reflect a pharmacodynamic change of diazepam remains unconfirmed by our study.
Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions.. Eva Bredberg; Tommy B Andersson; Lars Frison; Annelie Thuresson; Susanne Johansson; Maria Eriksson-Lepkowska; Marita Larsson; Ulf G Eriksson (2003) Clinical pharmacokinetics display abstract
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.