In vitro–in vivo extrapolation (IVIVE) using human liver microsomes has been widely used to predict metabolic clearance, but some of the factors used in the process of prediction show variability for the same compound: notably, microsomal intrinsic clearance values corrected by the unbound fraction (CL_{int, u}), physiological parameters used for scale-up, and the source of in vivo clearance data.

The purpose of this study was to assess the correlation between in vitro and in vivo CL_int with a focus on factors showing variability using four cytochrome P450 (CYP)3A substrates.

We surveyed in vivo clearance values in literature and also determined the microsomal CL_{int, u} values. A scaling factor (SF_direct) was defined as in vivo CL_int divided by the microsomal CL_{int, u}, which ranged from 1190 to 2310 (mg protein per kg body weight). The application of a mean SF_direct of 1600 (mg protein per kg body weight) and further normalization by the microsomal CL_{int, u} values of midazolam, the most commonly used substrate, resulted in improved prediction accuracy for CL_{int, u} values from various microsomal batches.

The results suggest the normalization of variability might be useful for predicting the in vivo CL_int.

使用人肝微粒体的体外–体内外推法（IVIVE）已广泛用于预测代谢清除率，但是在预测过程中使用的一些因素显示了同一化合物的变异性：值得注意的是，微粒体的固有清除率值已通过未结合的方法进行了校正分数（CL _int，u），用于放大的生理参数以及体内清除率数据的来源。

这项研究的目的是评估体外和体内CL _int之间的相关性，重点是使用四种细胞色素P450（CYP）3A底物显示变异性的因素。

我们调查了文献中的体内清除率值，并确定了微粒体的CL _int，u值。比例因子（SF_直接）定义为体内CL _int除以微粒体CL _{int u}，其范围为1190至2310（mg蛋白每千克体重）。应用平均SF _Direct为1600（毫克蛋白/ kg体重）并通过微粒体CL _int进一步标准化，最常用的底物咪达唑仑的_u值提高了CL _int的预测精度_，来自各种指标的_u值微粒体批次。

结果表明，变异性的归一化可能对预测体内CL _int有用。