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Hepatic drug metabolism by CYP2D6 in critically ill adults with AKI: effect of phenotype and AKI severity
Intensive Care Medicine Experimental volume 3, Article number: A839 (2015)
Hepatic drug metabolism by cytochrome P450 type 3A (CYP3A) is impaired in patients with acute kidney injury (AKI) . The mechanisms underlying this are unclear. CYP2D6 is another clinically important hepatic CYP subtype, responsible for approximately 25% drug metabolism. Common phenotypic variation exists, the clinical relevance of which has not been previously demonstrated in the critically ill. Tramadol is a drug probe principally of CYP2D6 metabolism. M1 is formed by CYP2D6, and M2 by CYP3A4. In a pilot study, we showed that single time point determination of tramadol concentration 4 hours after IV tramadol bolus accurately predicts integral tramadol exposure and hence tramadol metabolism in critically ill adults .
We aimed to investigate if an association exists between CYP2D6 drug metabolism and AKI in critically ill adults. We also investigated the importance of genetically predicted CYP2D6 phenotype (poor, intermediate and extensive metabolisers) for drug metabolism in critically ill adults.
As part of a study of drug metabolism, 72 consented critically ill adults received IV 10mg tramadol bolus at t= 0. Serum was collected prior to injection and at 4 hours for determination of serum tramadol and tramadol metabolite concentration by HPLC/MS/MS. Blood was analysed for CYP2D6 genotype. Data were collected to determine AKI severity by KDIGO classification. Glomerular filtration rate was assessed by simultaneous 4 hour urinary creatinine clearance (4CrCl) measurements. The clinical study was approved by the local ethics committee.
Baseline characteristics did not vary between groups
The median serum tramadol concentration at 4 hours for KDIGO 0-3 were 31.4, 29.6, 27.3 and 33.4 respectively. No significant difference in tramadol concentration by KDIGO class (Kruskal Wallis, p = 0.78), AKI duration, serum creatinine or urea or 4CrCl was found.
Tramadol concentration and those of its metabolites varied significantly with CYP2D6 phenotype (Kruskal Wallis, p = 0.005 for Tramadol, p = 0.0002 for M1, p = 0.0008 for M2)
When CYP2D6 phenotypes (IM, EM) were considered individually, no effect of AKI was seen on tramadol concentration (p = 0.83 and 0.50, Kruskal-Wallis).
In contrast to CYP3A4, CYP2D6 metabolism does not appear to be affected by AKI severity or duration. Tramadol metabolism is strongly influenced by genetically predicted CYP2D6 phenotype in the critically ill and is likely to reflect wide variation in CYP2D6 substrate metabolism in general.
Dr Lane is supported by an ESICM Basic Sciences Award and St George´s Hospital Medical Charity Awards.
Kirwan CJ, et al: Intensive Care Med. 2012, 38 (1): 76-84. 10.1007/s00134-011-2360-8. Jan. Acute kidney injury reduces the hepatic metabolism of midazolam in critically ill patients
Lane K, et al: Using tramadol to measure CYP2D6 metabolism in critically ill adults. Intensive Care Med. 2014, 40 (8): 1177-8. 10.1007/s00134-014-3372-y.
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Lane, K., Dixon, J., Lee, T. et al. Hepatic drug metabolism by CYP2D6 in critically ill adults with AKI: effect of phenotype and AKI severity. ICMx 3 (Suppl 1), A839 (2015). https://doi.org/10.1186/2197-425X-3-S1-A839
- Acute Kidney Injury
- CYP2D6 Genotype
- Hepatic Drug Metabolism
- CYP2D6 Phenotype