Masica Andrew L, Mayo Gail, Wilkinson Grant R
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Clin Pharmacol Ther. 2004 Oct;76(4):341-9. doi: 10.1016/j.clpt.2004.07.003.
Previous studies have not demonstrated good correlations between various presumed phenotypic measures of in vivo cytochrome P450 (CYP) 3A activity. However, in reality, few have used appropriate and validated in vivo probes that consider the complexities of CYP3A. Accordingly, the disposition of 3 closely related benzodiazepines with extensive and similar CYP3A-mediated metabolism characteristics but different pharmacokinetics was investigated, and correlations between the drugs were examined.
The single-dose oral clearances of alprazolam, midazolam, and triazolam and the systemic clearances of the latter 2 drugs were separately determined in 21 healthy subjects (10 men) according to a randomized experimental design with a minimum 1-week period between the individual studies. An erythromycin breath test was also performed.
After intravenous administration, systemic clearance varied 3-fold compared with a 6-fold range in clearance after an oral dose for all 3 drugs. However, mean values differed markedly between the drugs, with the systemic clearance of midazolam being almost double that of triazolam (383 +/- 73 mL/min versus 222 +/- 54 mL/min). Oral clearances were even more dissimilar: alprazolam, 75 +/- 36 mL/min; triazolam, 360 +/- 195 mL/min; and midazolam, 533 +/- 759 mL/min. Estimates of CYP3A-mediated extraction by the intestine and liver indicated approximately equal contributions by both organs but larger values for midazolam than for triazolam, and these differences accounted for the differences in oral bioavailability, 30% +/- 13% versus 55% +/- 20%, respectively. Statistically significant ( P = .001 to .004) correlations between the 3 drugs' oral clearances ranged from 0.60 to 0.68 ( r s value), whereas the correlation for the systemic clearances of midazolam and triazolam was 0.66 ( P = .001). No statistically significant relationships were observed between any of the clearance parameters and the erythromycin breath test.
Despite alprazolam, midazolam, and triazolam having markedly different pharmacokinetic characteristics, statistically significant correlations were present between the oral and systemic clearances of the 3 drugs, consistent with a major involvement of CYP3A in their metabolism and elimination. However, the magnitude of the coefficients of determination ( r s ) was such to suggest that an in vivo probe approach, even with the use of valid phenotypic trait values, will be unable to accurately and reliably predict the pharmacokinetic behavior of another CYP3A substrate, as determined by the enzyme's constitutive activity.
既往研究未证实体内细胞色素P450（CYP）3A活性的各种假定表型指标之间存在良好的相关性。然而，实际上，很少有研究使用适当且经过验证的体内探针来考虑CYP3A的复杂性。因此，研究了3种具有广泛且相似的CYP3A介导代谢特征但药代动力学不同的密切相关苯二氮䓬类药物的处置情况，并检测了这些药物之间的相关性。
根据随机实验设计，在21名健康受试者（10名男性）中分别测定阿普唑仑、咪达唑仑和三唑仑的单剂量口服清除率以及后2种药物的全身清除率，各单项研究之间至少间隔1周。还进行了红霉素呼气试验。
静脉给药后，所有3种药物的全身清除率变化了3倍，而口服给药后的清除率范围为6倍。然而，各药物的平均值差异显著，咪达唑仑的全身清除率几乎是三唑仑的两倍（383±73 mL/min对222±54 mL/min）。口服清除率差异更大：阿普唑仑为75±36 mL/min；三唑仑为360±195 mL/min；咪达唑仑为533±759 mL/min。肠道和肝脏对CYP3A介导的提取率估计表明，两个器官的贡献大致相等，但咪达唑仑的值高于三唑仑，这些差异导致了口服生物利用度的差异，分别为30%±13%和55%±20%。3种药物口服清除率之间的统计学显著相关性（P = 0.001至0.004）范围为0.60至0.68（rs值），而咪达唑仑和三唑仑全身清除率的相关性为0.66（P = 0.001）。在任何清除率参数与红霉素呼气试验之间均未观察到统计学显著关系。
尽管阿普唑仑、咪达唑仑和三唑仑具有明显不同的药代动力学特征，但这3种药物的口服和全身清除率之间存在统计学显著相关性，这与CYP3A在其代谢和消除过程中的主要作用一致。然而，决定系数（rs）的大小表明，即使使用有效的表型特征值，体内探针方法也无法准确可靠地预测另一种CYP3A底物的药代动力学行为，这是由该酶的组成活性所决定的。
