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目的:研究中国男性健康受试者口服咪达唑仑后其1＇-羟化代谢的药代动力学规律,并寻找适合的单个采血点血浆中1＇-羟化咪达唑仑/咪达唑仑的浓度比值来反映咪达唑仑的血浆清除率。方法:10名受试者禁食8小时后清晨空腹口服7.5mg咪达唑仑,利用非房室模型计算药代动力学参数。结果:咪达唑仑药代动力学参数C_(max)为(191±17)nmol/L,t_(max)为(1.01±0.14)h,t_(1/2)为(3.2±0.4)h,AUC_(0→∞)为(681±43)nmol·h·L~(-1),Cl_(oral)为(0.54±0.04)L/(h·kg),K_e为(0.2415±0.0021)h~(-1),K_α为(0.82±0.18)h~(-1)。1小时血浆中咪达唑仑与其代谢产物1＇-羟化咪达唑仑的比值与其清除率的相关性统计学上具有显著意义(r=0.7,P<0.05,n=10)。结论:可用口服咪达唑仑后1小时单个采血点的代谢产物1＇-羟化咪达唑仑与咪达唑仑浓度的比值来反映其血浆清除率,应用于CYP3A活性测定的人群试验。
OBJECTIVE: To study the pharmacokinetics of 1’-hydroxylated metabolites in Chinese male healthy subjects after midazolam oral administration and find suitable 1’-hydroxymidazolam / Azole concentration ratio to reflect the plasma clearance of midazolam. METHODS: Ten subjects were fasted for an early morning fasting dose of 7.5 mg midazolam 8 hours after fasting, and pharmacokinetic parameters were calculated using a non-compartmental model. Results: The maximal pharmacokinetic parameters of midazolam were (191 ± 17) nmol / L, t (max) were (1.01 ± 0.14) h and t 1/2 was (3.2 ± 0.4) h , The mean value of AUC_ (0 → ∞) was (681 ± 43) nmol · h · L -1, and the oral mean was 0.54 ± 0.04 L / (h · kg) and the K_e was 0.2415 ± 0.0021 h ~ (-1), K_α was (0.82 ± 0.18) h ~ (-1). The correlation between the ratio of midazolam to its metabolite 1’-hydroxymidazolam in 1 hour and its clearance rate was statistically significant (r = 0.7, P <0.05, n = 10). CONCLUSIONS: The ratio of 1’-hydroxymidazolam to midazolam, a metabolite of single blood sampling point 1 hour after oral midazolam, can be used to reflect the plasma clearance rate and be used in the population test of CYP3A activity determination.