Alrubia Sarah, Achour Brahim, Al-Majdoub Zubida M, Rostami-Hodjegan Amin, Barber Jill
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK.
Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Br J Clin Pharmacol. 2025 Jul;91(7):2028-2044. doi: 10.1002/bcp.70019. Epub 2025 Mar 4.
The aim of study was to generate quantitative data on the abundance of drug-metabolizing enzymes and transporters (DMETs) in inflamed and non-inflamed Crohn's disease (CD) ileum and colon, for incorporation into physiologically based pharmacokinetic (PBPK) models, enabling prediction of oral drugs' pharmacokinetics (PK) perturbation in CD patients.
Homogenate fractions were processed from 13 inflamed (six ileum and seven colon) and seven non-inflamed (two ileum and five colon) CD and 10 healthy (five ileum and five colon) tissues from deceased subjects by calcium chelation elution, and protein abundances determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics and compared with healthy values. PBPK simulation was applied to predict the potential effect of altered DMET profiles on the PK of oral drugs.
All investigated proteins showed trends for reduced expression in inflamed and non-inflamed CD samples relative to healthy individuals. Significant downregulation (P < 0.05) was observed for CYP3A4, AOX1, NAT1 and several SULTs in inflamed ileum as well as UGT1A10, NAT1, BCRP and several SULTs in inflamed and non-inflamed colon. Inter-individual variability was generally higher in CD, with exceptions, for most targets (up to 146%CV in inflamed ileum and up to 169% in histologically normal colon tissues). Integration of abundance data into a verified PBPK model of CD showed a considerable (≥2-fold; CD predicted relative to healthy predicted) change in systemic drug exposure for 10 drugs examined.
CD inflammation significantly suppresses the expression of intestinal DMETs, which, together with changes in other system parameters, can alter the fate of drugs taken orally in these patients. Virtual patients within a PBPK framework, informed by the measured DMET ranges in the intestine, may serve as a guide for dose adjustment in the absence of dedicated clinical studies.
本研究旨在生成关于炎症性和非炎症性克罗恩病（CD）回肠和结肠中药物代谢酶和转运蛋白（DMETs）丰度的定量数据，以纳入基于生理的药代动力学（PBPK）模型，从而预测CD患者口服药物的药代动力学（PK）扰动。
通过钙螯合洗脱法从13例炎症性（6例回肠和7例结肠）和7例非炎症性（2例回肠和5例结肠）CD患者以及10例已故健康受试者（5例回肠和5例结肠）的组织中制备匀浆组分，并通过基于液相色谱-串联质谱（LC-MS/MS）的蛋白质组学测定蛋白质丰度，并与健康值进行比较。应用PBPK模拟来预测DMET谱改变对口服药物PK的潜在影响。
与健康个体相比，所有研究的蛋白质在炎症性和非炎症性CD样本中均呈现表达降低的趋势。在炎症性回肠中观察到CYP3A4、AOX1、NAT1和几种SULTs显著下调（P < 0.05），在炎症性和非炎症性结肠中观察到UGT1A10、NAT1、BCRP和几种SULTs显著下调。CD患者的个体间变异性通常更高，但大多数靶点除外（炎症性回肠中高达146%CV，组织学正常结肠组织中高达169%）。将丰度数据整合到经过验证的CD患者PBPK模型中，显示所检测的10种药物的全身药物暴露有相当大的变化（≥2倍；CD预测值相对于健康预测值）。
CD炎症显著抑制肠道DMETs的表达，这与其他系统参数的变化一起，可改变这些患者口服药物的命运。在PBPK框架内，根据肠道中测量的DMET范围构建的虚拟患者，可在缺乏专门临床研究的情况下作为剂量调整的指导。
