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This study aims to quantify drug‐metabolising enzymes, transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) patients.

Microsomal fractionation was performed and pooled microsomes were prepared. Global and accurate mass and retention time liquid chromatography–mass spectrometry proteomics were used to quantify proteins. A QconCAT (KinCAT) for the quantification of RTKs was designed and applied for the first time. Physiologically based pharmacokinetic (PBPK) simulations were performed to assess the contribution of altered abundance of drug‐metabolising enzymes and transporters to changes in pharmacokinetics.

Most CYPs and UGTs were downregulated in histologically normal relative to …