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 th e pharmacokinetics of drugs metabolized through CYP 3A4. Losartan, an angio tensin II antagonist, is converted into its main active metabolite E3174 by CYP 3A4 and CYP 2C9. The effect of GJ on losartan pharmacokinetics was ass essed in a randomized crossover trial. Losartan was given to 9 volunteers w ith and without GJ. Concentrations of losartan and its E3174 metabolite wer e determined in serum by a highperformance liquid chromatography method (HP LC). Significant differences were observed in some of the pharmacokinetic p arameters of losartan and its metabolite E3174 after losartan administratio n with and without co-administered GJ. The lag time (time to drug appearanc e in serum) of losartan increased significantly with coadministered GJ. The mean residence time (MRT) and half-life (t(1/2)) of the E3174 metabolite w ere significantly longer and the area under the concentration-time curve (A UC) of the E3174 metabolite was significantly smaller after concomitant GJ administration. The ratio AUC(losartan)/AUC(E3174) was significantly increa sed after concurrent grapefruit juice intake. The increased lag time of los artan and the increased MRT and t(1/2) and decreased AUC of E3174 were cons idered indicative of simultaneous CYP 3A4 inhibition and P-glycoprotein act ivation. The significantly increased AUC(losartan)/AUC(E3174) ratio, howeve r, indicates reduced losartan conversion to E3174 by CYP 3A4 metabolism as a result of co-administered GJ.