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The rs776746 variant of CYP3A5 is associated with intravenous midazolam plasma levels and higher clearance in critically ill Mexican paediatric patients
Author(s) -
FloresPérez Carmen,
CastillejosLópez Manuel de Jesús,
ChávezPacheco Juan Luis,
DávilaBorja Víctor Manuel,
FloresPérez Janett,
ZárateCastañón Patricia,
AcostaBastidas Mario,
CruzEscobar Jonathan,
TorresEspíndola Luz María
Publication year - 2021
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/jcpt.13388
Subject(s) - midazolam , cyp3a5 , genotype , pharmacokinetics , cyp3a4 , single nucleotide polymorphism , pharmacology , chemistry , medicine , allele , cytochrome p450 , gene , biochemistry , metabolism , sedation
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 (Q 25 0.01–Q 75 196.09), whereas patients with the allelic variant (TT+TC) had a median midazolam concentration of 320.3 ng/ml (Q 25 37.51–Q 75 529.51), p = 0.001. The median pharmacokinetic clearance rates were 0.10 L/kg/h (Q 25 0.01–Q 75 0.34) in patients with the allelic variant (TT+TC) and 0.03 L/kg/h (Q 25 0.002–Q 75 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.