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Sex and Age Influence on Association of CYP450 Polymorphism with Midazolam Levels in Critically Ill Children.

ABSTRACT: Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The present study aimed to determine the sex and age influence on association of CYP450 polymorphism with midazolam levels in critically ill children. Seventy-two DNA samples were genotyped by real-time PCR. Children ≤ five years of age who carry the rs776746 (T) allele in CYP3A5 gene were associated with lower plasma midazolam levels. The concentration median in patients was 0.0 ng/mL, while in patients with the normal (C) allele, it was 438.17 ng/mL (Q₂₅ 135.75-Q₇₅ 580.24), p = 0.005. The midazolam plasmatic concentration in female patients with the minor (T) allele was 0.0 ng/mL (Q₂₅0.00-Q₇₅204.3), while in patients with the normal (C) allele median it was 459.0 ng/mL (Q₂₅296.9-Q₇₅789.7), p = 0.002. Analysis of the dominant model for the rs2740574 variant in CYP3A4 revealed a median of 0.38 L/kg (Q₂₅0.02-Q₇₅1.5) for the volume of distribution parameter in female patients with the normal T allele, while female patients with the minor C allele showed a median of 18.1 L/kg (Q₂₅7.5-Q₇₅28.7) p = 0.02. Our results suggest an altered midazolam metabolism due to the presence the allelic rs2740574 variants of CYP3A4 and rs776746 of CYP3A5, and also the strong influence of age and sex.

SUBMITTER: Flores-Perez C

PROVIDER: S-EPMC9689687 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Sex and Age Influence on Association of <i>CYP450</i> Polymorphism with Midazolam Levels in Critically Ill Children.

Flores-Pérez Carmen C Flores-Pérez Janett J de Jesús Castillejos López Manuel M Chávez-Pacheco Juan Luis JL Tejada-Gutiérrez Karla Miroslava KM Aquino-Gálvez Arnoldo A Torres-Espíndola Luz María LM

Diagnostics (Basel, Switzerland) 20221115 11

Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The present study aimed to determine the sex and age influence on association of CYP450 polymorphism with midazolam levels in critically ill children. Seventy-two DNA samples were genotyped by real-time PCR. Children ≤ five years of age who carry the rs776746 (T) allele in <i>CYP3A5</i> gene were associated with lower plasma midazolam levels. The concentration median in patients was 0.0 n ...[more]

PMID: 36428856

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Project description:OBJECTIVES:Low mannose-binding lectin levels and haplotypes associated with low mannose-binding lectin production have been associated with infection and severe sepsis. We tested the hypothesis that mannose-binding lectin levels would be associated with severe infection in a large cohort of critically ill children. DESIGN:Prospective cohort study. SETTING:Medical and Surgical PICUs, Boston Children's Hospital. PATIENTS:Children less than 21 years old admitted to the ICUs from November 2009 to November 2010. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We measured mannose-binding lectin levels in 479 of 520 consecutively admitted children (92%) with severe or life-threatening illness. We genotyped 213 Caucasian children for mannose-binding lectin haplotype tagging variants and assigned haplotypes. In the univariate analyses of mannose-binding lectin levels with preadmission characteristics, levels were higher in patients with preexisting renal disease. Patients who received greater than 100?mL/kg of fluids in the first 24 hours after admission had markedly lower mannose-binding lectin, as did patients who underwent spinal fusion surgery. Mannose-binding lectin levels had no association with infection status at admission, or with progression from systemic inflammatory response syndrome to sepsis or septic shock. Although mannose-binding lectin haplotypes strongly influenced mannose-binding lectin levels in the predicted relationship, low mannose-binding lectin-producing haplotypes were not associated with increased risk of infection. CONCLUSIONS:Mannose-binding lectin levels are largely genetically determined. This relationship was preserved in children during critical illness, despite the effect of large-volume fluid administration on mannose-binding lectin levels. Previous literature evaluating an association between mannose-binding lectin levels and severe infection is inconsistent; we found no relationship in our PICU cohort. We found that mannose-binding lectin levels were lower after aggressive fluid resuscitation and suggest that studies of mannose-binding lectin in critically ill patients should assess mannose-binding lectin haplotypes to reflect preillness levels.

Dataset Information

Sex and Age Influence on Association of CYP450 Polymorphism with Midazolam Levels in Critically Ill Children.

Publications

Sex and Age Influence on Association of <i>CYP450</i> Polymorphism with Midazolam Levels in Critically Ill Children.

Similar Datasets

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