title: Acute kidney injury reduces the hepatic metabolism of midazolam in critically ill patients.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: General Intensive Care, St George's Hospital, NHS Trust, Blackshaw Road, London SW17 0QT, UK. cjkirwan100@msn.com
authors: C J
authors: CJ
authors: Kirwan
authors: I A M
authors: IA
authors: MacPhee
authors: T
authors: T
authors: Lee
authors: D W
authors: DW
authors: Holt
authors: B J
authors: BJ
authors: Philips
mesh_terms: D058186:Acute Kidney Injury / Q000503:physiopathology*; D018686:Anesthetics, Intravenous / Q000097:blood / Q000378:metabolism*; D016638:Critical Illness; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008874:Midazolam / Q000097:blood / Q000378:metabolism*; D011237:Predictive Value of Tests; D012720:Severity of Illness Index
chemical_list: D018686:Anesthetics, Intravenous; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam