Sirisuth Nattee, Eddington Natalie D
Pharmacokinetics Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore 21201, USA.
Eur J Pharm Biopharm. 2002 May;53(3):301-9. doi: 10.1016/s0939-6411(01)00248-x.
To investigate the influence of alpha-hydroxymetoprolol (AHM) and 4-(2-hydroxy-3-isopropylaminopropoxy)-phenylacetic acid (ACMB), both derived from its first pass metabolism of metoprolol, an in vitro in vivo correlation incorporating first pass metabolite data for metoprolol extended release formulations was developed. Three different releasing formulations (slow (S), moderate (M) and fast (F), 100 mg) of metoprolol were evaluated in a previously reported clinical study. The non-first pass effect (Non-FPE) in vitro in vivo correlation (IVIVC) was developed using a fraction of metoprolol dissolved and a fraction of total drug (metoprolol + metabolites) as the absorption data for various combinations of formulations (S/M/F, M/F, S/M, and S/F). Direct convolution approaches predicting metoprolol concentrations and indirect convolution predicting total drug concentrations (metoprolol + metabolites) were used to determine in vivo behavior. The Non-FPE IVIVC using the S/M/F formulations displayed the strongest relationship (r2 > 0.92). The IVIVC using the indirect approach was predictive of both the C(max) (prediction errors (PE) 4.77, 3.94 and 6.14%) and AUC (10.7, 11.0 and 11.3%) for metoprolol, AHM and ACMB. Poor predictability (PE > 40% for C(max) and AUC) was observed for metoprolol when using the direct methods. The predictability of the IVIVC using the indirect approach as compared to the direct method displays the influence of first pass metabolism on the development and evaluation of an IVIVC for a drug that displays a high extraction ratio. In addition, the indirect IVIVC allows for not only predicting the in vivo performance of the parent drug but also the metabolites formed via the first pass effect.
为研究美托洛尔首过代谢产物α-羟基美托洛尔（AHM）和4-(2-羟基-3-异丙氨基丙氧基)-苯乙酸（ACMB）的影响，建立了一个包含美托洛尔缓释制剂首过代谢产物数据的体外-体内相关性模型。在一项先前报道的临床研究中，对三种不同释放制剂（慢速（S）、中速（M）和快速（F），100 mg）的美托洛尔进行了评估。使用溶解的美托洛尔部分和总药物（美托洛尔+代谢产物）部分作为各种制剂组合（S/M/F、M/F、S/M和S/F）的吸收数据，建立了非首过效应（Non-FPE）体外-体内相关性（IVIVC）。采用预测美托洛尔浓度的直接卷积法和预测总药物浓度（美托洛尔+代谢产物）的间接卷积法来确定体内行为。使用S/M/F制剂的Non-FPE IVIVC显示出最强的相关性（r2>0.92）。采用间接法的IVIVC能够预测美托洛尔、AHM和ACMB的C(max)（预测误差（PE）分别为4.77%、3.94%和6.14%）和AUC（分别为10.
