The rs776746 variant of CYP3A5 is associated with intravenous midazolam plasma levels and higher clearance in critically ill Mexican paediatric patients.

WHAT IS KNOWN AND OBJECTIVE: Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The presence of single-nucleotide polymorphisms (SNPs) in the genes encoding these enzymes, such as CYP3A4*1B which is associated with low enzyme expression and activity and CYP3A5*3, has been associated with decrease in enzymatic activity and reduced drug clearance, with potential effects on drug levels and/or toxicity. The present study was conducted to determine the frequencies of the allelic variants of the CYP3A4 (rs2740574) and CYP3A5 (rs776746) genes and their effects on the plasma levels and clearance of intravenous midazolam in critically ill Mexican paediatric patients. METHODS: Seventy-two DNA samples were genotyped by real-time PCR with TaqMan probes. Plasma midazolam levels were determined at 3 and 24 h post infusion by high-performance liquid chromatography. RESULTS AND DISCUSSION: The allelic variant rs776746 (CYP3A5*3) was associated with high midazolam plasma levels; the median concentration in patients with the normal genotype (CC) <0.01 ng/ml (Q25 0.01-Q75 196.09), whereas patients with the allelic variant (TT+TC) had a median midazolam concentration of 320.3 ng/ml (Q25 37.51-Q75 529.51), p = 0.001. The median pharmacokinetic clearance rates were 0.10 L/kg/h (Q25 0.01-Q75 0.34) in patients with the allelic variant (TT+TC) and 0.03 L/kg/h (Q25 0.002-Q75 0.13) in patients with the normal genotype (CC), p = 0.042. WHAT IS NEW AND CONCLUSION: This is the first study that reports the frequency of the rs776746 polymorphism in critically ill paediatric patients, which is relevant, since carriers of the *1 allele synthesizing a functional enzyme may need higher doses to achieve adequate sedation. Our results show that compared with carriers of the normal allele, patients with the CYP3A5*3 allelic variant (rs776746) had increased plasma midazolam levels at 3 h after infusion discontinuation (320.3 ng/ml) and greater clearance (0.10 L/kg/h) of the drug.