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Title: Hepatic drug metabolism in critically ill adults with acute kidney injury
Author: Lane, Katie
ISNI:       0000 0004 7427 1284
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2018
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Background: Acute Kidney Injury (AKI) is a common problem in critical care with its remote organ effects contributing to the high morbidity and mortality. Animal evidence has found deranged hepatic drug metabolism by cytochrome P450 enzymes (CYP) in AKI. The two most clinically relevant CYPs in humans are CYP3A and CYP2D6. Using midazolam as a probe drug, CYP3A metabolism was impaired in adults with AKI. Patients expressing functional CYP3A5 were protected from this effect. We investigated the factors and mechanisms affecting CYP3A and CYP2D6- mediated drug metabolism in the critically ill with AKI. Methods: A prospective pilot determined whether single time point tramadol concentration following intravenous bolus was a reliable surrogate for integral tramadol exposure in critically ill adults. A larger clinical study was performed using midazolam and tramadol as drug probes of CYP3A and CYP2D6 respectively. Participants received sequential doses and concentration monitoring. CYP3A5 and CYP2D6 genotype and serum cytokine profile were determined. Participant serum was applied to human hepatocytes in vitro and CYP transcription, translation and enzymatic activity assessed. Results: Single determination of tramadol concentration correlated with integral tramadol exposure (rs=0.983; p<0.0001). CYP2D6 metabolism was unchanged by AKI severity (p=0.73), but correlated strongly with genotype (p=0.002). Single study day midazolam concentration and AKI severity were not associated. In patients with worsening AKI, CYP3A metabolism may deteriorate over time (p=0.037) but patients expressing CYP3A5*1 were protected. Midazolam and tramadol concentration were correlated in the clinical study (rs=0.546; p<0.0001). CYP3A4 mRNA doubled (p=0.018), but CYP3A protein was unchanged when hepatocytes were exposed to serum from patients with AKI compared to those without. Conclusions: CYP3A metabolism may decrease with AKI severity and duration, while CYP2D6 metabolism was unchanged. CYP3A5 and CYP2D6 genotype are important determinants of CYP activity. Few conclusions were ascertained from laboratory studies, although CYP3A transcription increased with AKI severity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available