Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers.

Grapefruit juice (GJ), a cytochrome P450 (CYP) 3A4 inhibitor, may affect the pharmacokinetics of drugs metabolized through CYP 3A4. Losartan, an angiotensin II antagonist, is converted into its main active metabolite E3174 by CYP 3A4 and CYP 2C9. The effect of GJ on losartan pharmacokinetics was assessed in a randomized crossover trial. Losartan was given to 9 volunteers with and without GJ. Concentrations of losartan and its E3174 metabolite were determined in serum by a high-performance liquid chromatography method (HPLC). Significant differences were observed in some of the pharmacokinetic parameters of losartan and its metabolite E3174 after losartan administration with and without co-administered GJ. The lag time (time to drug appearance in serum) of losartan increased significantly with co-administered GJ. The mean residence time (MRT) and half-life (t(1/2)) of the E3174 metabolite were significantly longer and the area under the concentration--time curve (AUC) of the E3174 metabolite was significantly smaller after concomitant GJ administration. The ratio AUC(losartan)/AUC(E3174) was significantly increased after concurrent grapefruit juice intake. The increased lag time of losartan and the increased MRT and t1/2 and decreased AUC of E3174 were considered indicative of simultaneous CYP 3A4 inhibition and P-glycoprotein activation. The significantly increased AUC(losartan)/AUC(E3174) ratio, however, indicates reduced losartan conversion to E3174 by CYP 3A4 metabolism as a result of co-administered GJ.

Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial.

BACKGROUND: Excess cardiovascular mortality has been documented in chronic haemodialysis patients. Oxidative stress is greater in haemodialysis patients with prevalent cardiovascular disease than in those without, suggesting a role for oxidative stress in excess cardiovascular disease in haemodialysis. We investigated the effect of high-dose vitamin E supplementation on cardiovascular disease outcomes in haemodialysis patients with pre-existing cardiovascular disease. METHODS: Haemodialysis patients with pre-existing cardiovascular disease (n=196) aged 40-75 years at baseline from six dialysis centres were enrolled and randomised to receive 800 IU/day vitamin E or matching placebo. Patients were followed for a median 519 days. The primary endpoint was a composite variable consisting of: myocardial infarction (fatal and non-fatal), ischaemic stroke, peripheral vascular disease (excluding the arteriovenous fistula), and unstable angina. Secondary outcomes included each of the component outcomes, total mortality, and cardiovascular-disease mortality. FINDINGS: A total of 15 (16%) of the 97 patients assigned to vitamin E and 33 (33%) of the 99 patients assigned to placebo had a primary endpoint (relative risk 0.46 [95% CI 0.27-0.78], p=0.014). Five (5.1%) patients assigned to vitamin E and 17 (17.2%) patients assigned to placebo had myocardial infarction (0.3 [0.11-0.78], p=0.016). No significant differences in other secondary endpoints, cardiovascular disease, or total mortality were detected. INTERPRETATION: In haemodialysis patients with prevalent cardiovascular disease, supplementation with 800 IU/day vitamin E reduces composite cardiovascular disease endpoints and myocardial infarction.