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Expression and Function of Hepatic Drug Metabolizing Enzymes and Transport Proteins in Livers of Patients with End‐Stage Renal Disease (ESRD)
Author(s) -
Feere David Alexander,
Velenosi Thomas,
Gaspar Melisa Lynn,
Urquhart Brad
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.670.1
Subject(s) - chlorzoxazone , tolbutamide , end stage renal disease , cyp3a4 , liver disease , dextromethorphan , medicine , pharmacology , cyp2c9 , renal function , drug , disease , chemistry , endocrinology , cytochrome p450 , cyp2e1 , diabetes mellitus , metabolism
Objectives This study aims to determine the changes in expression and function of hepatic drug metabolizing enzymes (DMEs) and drug transport proteins in liver samples from patients with end‐stage renal disease (ESRD). Methods Liver samples were collected from nine recently deceased patients with ESRD and six recently deceased controls. Relative gene expression of DMEs and transport proteins were determined by qPCR. Results P‐gp and CYP2E1 expression were significantly decreased (P<0.05) in ESRD livers compared to control livers (21% and 17% of control, respectively). There was a trend of decreased expression of CYP2D6, CYP2C9, OATP1B1 MRP2 and MRP3, although this failed to reach significance. Conclusions Our results demonstrate that DMEs and transport proteins are down‐regulated in ESRD. Current studies are evaluating the enzymatic activity of DMEs in hepatic microsomes from ESRD patients using the specific probe substrates midazolam (CYP3A4), tolbutamide (CYP2C9), chlorzoxazone (CYP2E1) and dextromethorphan (CYP2D6). Our results help explain the large decrease in non‐renal drug clearance observed in patients with ESRD. This research is supported by the Lawson Health Research Institute.