中华生物医学工程杂志
中華生物醫學工程雜誌
중화생물의학공정잡지
CHINESE JOURNAL OF BIOMEDICAL ENGINEERING
2012年
4期
260-264
,共5页
异黄酮类%药代动力学%咪达唑仑%金雀异黄酮%基因多态性
異黃酮類%藥代動力學%咪達唑崙%金雀異黃酮%基因多態性
이황동류%약대동역학%미체서륜%금작이황동%기인다태성
Isoflavones%Pharmacokinetics%Midazolam%Genistein%Gene polymorphism
目的 探讨金雀异黄酮在体内对不同细胞色素酶P450(CYP3A)基因型健康受试者咪达唑仑药代动力学的影响.方法 基因分型筛选CY P3A5* 1/CYP3A5*1、CYP3A5* 1/CYP3A5*3及CYP3A5*3/CYP3A5*3基因型健康受试者各6例.临床试验按照两阶段交叉方案进行:第一阶段18例受试者按随机数字表法分为2组,每组9例,受试者给予金雀异黄酮片或安慰剂口服处理14d,第15天所有受试者口服咪达唑仑.经过14d洗脱期后第二阶段交叉重复试验,分别于口服咪达唑仑后0、0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、12、24、36 h时间点抽取血样,高效液相色谱-串联质谱法测定咪达唑仑药代动力学参数.结果 经金雀异黄酮处理后,CY P3A5* 1/CYP3A5*1、CYP3A5* 1/CYP3A5*3基因型受试者咪达唑仑0～36h药物浓度-时间曲线下面积(AUC0→36)明显降低[(120.10±40.28)ng·h·ml-1比( 140.65±55.40)ng·h· ml-1,(110.50±38.14)ng·h·ml-1比( 138.56±30.26)ng·h ·ml-1,均P＜0.05 ]; AUCo→∞亦显著降低[(172.49±56.32) ng·h·ml-1比(229.48±82.61)ng·h·ml-1,(185.96±74.21)ng·h·ml- 1比(286.43±35.62)ng·h·ml-1,均P＜0.05];药物消除半衰期(t1/2)显著缩短[(1.54±0.96)h比(4.01±2.68)h,(1.29±0.87)h比(3.59±1.99)h,均P＜0.05],但对CYP3A5*3/CYP3A5*3基因型受试者咪达唑仑的药代动力学没有影响.结论 金雀异黄酮对CYP3A5* 1/C YP3A5*1、CYP3A5* 1/CYP3A5*3基因型健康受试者咪达唑仑的代谢具有显著的影响.
目的 探討金雀異黃酮在體內對不同細胞色素酶P450(CYP3A)基因型健康受試者咪達唑崙藥代動力學的影響.方法 基因分型篩選CY P3A5* 1/CYP3A5*1、CYP3A5* 1/CYP3A5*3及CYP3A5*3/CYP3A5*3基因型健康受試者各6例.臨床試驗按照兩階段交扠方案進行:第一階段18例受試者按隨機數字錶法分為2組,每組9例,受試者給予金雀異黃酮片或安慰劑口服處理14d,第15天所有受試者口服咪達唑崙.經過14d洗脫期後第二階段交扠重複試驗,分彆于口服咪達唑崙後0、0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、12、24、36 h時間點抽取血樣,高效液相色譜-串聯質譜法測定咪達唑崙藥代動力學參數.結果 經金雀異黃酮處理後,CY P3A5* 1/CYP3A5*1、CYP3A5* 1/CYP3A5*3基因型受試者咪達唑崙0～36h藥物濃度-時間麯線下麵積(AUC0→36)明顯降低[(120.10±40.28)ng·h·ml-1比( 140.65±55.40)ng·h· ml-1,(110.50±38.14)ng·h·ml-1比( 138.56±30.26)ng·h ·ml-1,均P＜0.05 ]; AUCo→∞亦顯著降低[(172.49±56.32) ng·h·ml-1比(229.48±82.61)ng·h·ml-1,(185.96±74.21)ng·h·ml- 1比(286.43±35.62)ng·h·ml-1,均P＜0.05];藥物消除半衰期(t1/2)顯著縮短[(1.54±0.96)h比(4.01±2.68)h,(1.29±0.87)h比(3.59±1.99)h,均P＜0.05],但對CYP3A5*3/CYP3A5*3基因型受試者咪達唑崙的藥代動力學沒有影響.結論 金雀異黃酮對CYP3A5* 1/C YP3A5*1、CYP3A5* 1/CYP3A5*3基因型健康受試者咪達唑崙的代謝具有顯著的影響.
목적 탐토금작이황동재체내대불동세포색소매P450(CYP3A)기인형건강수시자미체서륜약대동역학적영향.방법 기인분형사선CY P3A5* 1/CYP3A5*1、CYP3A5* 1/CYP3A5*3급CYP3A5*3/CYP3A5*3기인형건강수시자각6례.림상시험안조량계단교차방안진행:제일계단18례수시자안수궤수자표법분위2조,매조9례,수시자급여금작이황동편혹안위제구복처리14d,제15천소유수시자구복미체서륜.경과14d세탈기후제이계단교차중복시험,분별우구복미체서륜후0、0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、12、24、36 h시간점추취혈양,고효액상색보-천련질보법측정미체서륜약대동역학삼수.결과 경금작이황동처리후,CY P3A5* 1/CYP3A5*1、CYP3A5* 1/CYP3A5*3기인형수시자미체서륜0～36h약물농도-시간곡선하면적(AUC0→36)명현강저[(120.10±40.28)ng·h·ml-1비( 140.65±55.40)ng·h· ml-1,(110.50±38.14)ng·h·ml-1비( 138.56±30.26)ng·h ·ml-1,균P＜0.05 ]; AUCo→∞역현저강저[(172.49±56.32) ng·h·ml-1비(229.48±82.61)ng·h·ml-1,(185.96±74.21)ng·h·ml- 1비(286.43±35.62)ng·h·ml-1,균P＜0.05];약물소제반쇠기(t1/2)현저축단[(1.54±0.96)h비(4.01±2.68)h,(1.29±0.87)h비(3.59±1.99)h,균P＜0.05],단대CYP3A5*3/CYP3A5*3기인형수시자미체서륜적약대동역학몰유영향.결론 금작이황동대CYP3A5* 1/C YP3A5*1、CYP3A5* 1/CYP3A5*3기인형건강수시자미체서륜적대사구유현저적영향.
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.
