Clinical Medical College, Yangzhou University, Yangzhou, China.
Institution of Drug Clinical Trial, Subei People's Hospital, Yangzhou, China.
Eur J Drug Metab Pharmacokinet. 2021 Mar;46(2):225-233. doi: 10.1007/s13318-020-00667-9.
Cytochrome P450 (CYP) enzymes are one of the main sources of variability in drug metabolic clearance. Information on their abundance levels is therefore crucial to optimize scaling factors for in vitro-in vivo extrapolation (IVIVE) to predict metabolic clearance.
This study aims to quantify the abundance data of hepatic drug-metabolizing CYP enzymes in East Asian subjects reported from various sources in the literature using meta-analysis.
We conducted a meta-analysis on the abundance of drug-metabolizing CYP enzymes in the liver of East Asian adults. Eligible reports were identified based on predefined criteria-(1) individual liver microsomal samples, and (2) absolute protein abundance data from normal tissues of East Asian adult subjects. Subgroup and sensitivity analyses were also performed.
Among the 11 CYP isoforms analyzed in East Asian subjects, CYP3A5 and CYP3A4 had the highest protein levels. In particular, the number of studies and the liver sample used to quantify the abundance of CYP3A4 were the largest. Of the isoforms involved, CYP2J2 and CYP2B6 had the lowest abundance level, i.e., <5 pmol/ mg of microsomal protein. For enzymes with abundance values available in both Chinese and Japanese subjects (CYP1A2, CYP2C9, CYP3A4, and CYP3A5), the abundance level of each CYP isoform appeared to be higher in Chinese than in Japanese subjects. The most distinct difference was observed in CYP3A5 abundance.
The current meta-analysis shows that the abundance levels of CYP enzymes appear to vary greatly among different East Asian individuals who have similar ethnic backgrounds and food habits. The pooled data of CYP abundance can be used as preliminary reference values along with the associated variations for the projections of pharmacokinetics through physiologically based pharmacokinetic (PBPK) approaches.
细胞色素 P450（CYP）酶是药物代谢清除率变异性的主要来源之一。因此，有关其丰度水平的信息对于优化体外-体内外推（IVIVE）的比例因子以预测代谢清除率至关重要。
本研究旨在使用荟萃分析量化文献中来自不同来源的东亚人群肝脏药物代谢 CYP 酶丰度数据。
我们对东亚成年人肝脏药物代谢 CYP 酶丰度进行了荟萃分析。根据预先设定的标准（1）个体肝微粒体样本，（2）东亚成年受试者正常组织的绝对蛋白丰度数据，确定符合条件的报告。还进行了亚组和敏感性分析。
在分析的 11 种 CYP 同工酶中，CYP3A5 和 CYP3A4 的蛋白水平最高。特别是，研究数量和用于定量 CYP3A4 丰度的肝样品种类最多。在所涉及的同工酶中，CYP2J2 和 CYP2B6 的丰度最低，即<5 pmol/ mg 微粒体蛋白。对于在中、日受试者中均有丰度值的同工酶（CYP1A2、CYP2C9、CYP3A4 和 CYP3A5），每个 CYP 同工酶的丰度水平似乎在中国受试者中高于日本受试者。最明显的差异发生在 CYP3A5 丰度上。
目前的荟萃分析表明，具有相似种族背景和饮食习惯的不同东亚个体之间 CYP 酶的丰度水平差异很大。CYP 丰度的汇总数据可作为初步参考值，并结合生理基于药代动力学（PBPK）方法进行药代动力学预测的相关变异性。
