Acute kidney injury reduces the hepatic metabolism of midazolam in critically ill patients
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Acute kidney injury (AKI) is a common and serious complication increasing morbidity and mortality from all causes of hospital admission. We have previously shown that AKI decreases midazolam metabolism, a substrate of the cytochrome P450 3A (CYP3A) enzymes and our primary aim was to determine if this effect is dependent on the severity of AKI. We also present preliminary data on the functional impact of different genotypes of CYP3A.
Critically ill patients at risk of AKI and admitted to a general intensive care unit were categorised after initial resuscitation according to the RIFLE criteria for AKI. Midazolam (1mg) was administered and the serum concentration of midazolam measured at 4 h. Samples were taken for CYP3A genotyping.
Seventy-three patients were assigned to categories R, I and F of the RIFLE criteria or C (controls). Midazolam concentrations (ng mL−1) increased significantly (p = 0.002) as the severity of AKI worsened [control 3.1 (1.4–5.9), risk 4.7 (1.3–10.3), injury 3.9 (2.0–11.1) and failure 6.8 (2.2–113.6)] and were predicted by the duration of AKI (p = 0.000) and γ-glutamyl transferase (p = 0.005) concentrations. Increasing BMI negatively predicted the midazolam concentration (p = 0.001). Preliminary data suggest this effect is diminished if the patient expresses functional CYP3A5.
Increasing severity and duration of AKI are associated with decreased midazolam elimination. We propose that this is caused by impaired CYP3A activity secondary to AKI. The exact mechanism remains to be elucidated. This may have important implications for our drug treatment of critically ill patients.
KeywordsAcute kidney injury Pharmacogenetics Cytochrome P450 Midazolam Hepatic metabolism Critical illness
The authors would like to thank the St George’s Research Fund for enabling the research to be done and Michelle Moreton of the Analytical Unit for helping us with the genotyping of the CYP 3A enzymes. Dr Christopher Kirwan was involved in the design, the recruitment of patients, collection of data and samples, analysis of data and writing of the manuscript. Dr Iain MacPhee was involved in the design and supervision of the research. Mr Terry Lee developed the midazolam assay and handled the samples. Professor David Holt developed the midazolam assay. Dr Barbara Philips was involved in the development and design of the research, the recruitment of patients, supervision of the study, analysis of the data and writing of the manuscript.
Conflict of interest
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