Effects of genistein on pharmacokinetics of midazolam in healthy volunteers with different genotypes

Abstract

Objective To investigate the effects of genistein on pharmacokinetics of midazolam in healthy volunteers with different cytochrome P450(CYP3A) genotypes.Methods Healthy volunteers with genotypes of CYP3A5*1/CYP3A5*1 (n=6),CYP3A5*1/CYP3A5*3 (n=6) or CYP3A5*3/CYP3A5*3 (n=6)underwent screening procedures and were assigned into a 2-stage cross-over clinical trial At stage one,all the subjects were allocated to 2 groups(n=9 each) by random digits table,and received a 14-day treatment of either genistein tablets or placebo followed by midazolam oral administration at day 15.Subsequent to a 14-day wash-out period,treatment of both groups was switched at stage two.Plasma was sampled at hour 0,0.25,0.5,0.75,1,1.5,2,2.5,3,4,6,8,12,24 and 36,respectively,following administration of midazolam.Pharmacokinetics was examined by high performance liquid chromatography-tandem mass spectrometry.Results Subjects with CYP3A5*1/CYP3A5*1 and CYP3A5*1/CYP3A5*3 genotypes yielded significantly lower area under curve of midazolam concentration from hour 0 to 36 (AUCo→36) [ (120.10±40.28)ng·h·ml-1 vs (140.65±55.40)ng·h·ml- 1,(110.50±38.14)ng·h·ml- 1vs (138.56±30.26)ng·h·ml-1,both P＜0.05],markedly reduced AUC0→∞ also [ ( 172.49±56.32)ng· h· ml-1 vs (229.48±82.61) ng· h· ml- 1,(185.96±74.21)ng·h·ml- 1 vs (286.43±35.62)ng·h·ml- 1,both P＜0.05],and considerably shortened elimination half-life (t1/2) [ (1.54 ± 0.96) h vs (4.01 ± 2.68) h,(1.29 ± 0.87) h vs (3.59 ± 1.99) h,both P＜0.05].Contrarily,pharmacokinetic parameters of midazolam were unaffected in subjects with CYP3A5*3/CYP3A5*3 genotype.Conclusion Genistein may markedly in fluence the metabolism of midazolam in healthy subjects with CYP3A5* 1/CYP3A5* 1 and CYP3A5*1/CYP3A5*3 genotypes. Key words: Isoflavones; Pharmacokinetics; Midazolam; Genistein; Gene polymorphism