Evaluation of urinary acetaminophen metabolites and its association with the genetic polymorphisms of the metabolising enzymes, and serum acetaminophen concentrations in preterm neonates with patent ductus arteriosus
Creators: name: Sridharan, Kannan
name: Jufairi, Muna Al
name: Ansari, Eman Al
name: Jasim, Anfal
name: Diab, Diab Eltayeb
name: Marzooq, Reem Al
name: Madhoob, Abdulraoof Al
Publisher: name: Taylor & Francis
Year: 2021
Subjects: subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: 59999 Environmental Sciences not elsewhere classified
subject: FOS: Earth and related environmental sciences
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: Immunology
subject: FOS: Clinical medicine
subject: Cancer
subject: Hematology
subject: 60506 Virology
subject: Computational Biology

description: Acetaminophen is gaining importance as a first-line drug for treating patent ductus arteriosus (PDA) in neonates. Predominant metabolites of acetaminophen in preterm neonates vary from that of adults; and the drug is predominantly metabolised by conjugation and partly by Cytochrome P450 (CYP) enzymes.We carried out the present study to identify the principal urine metabolites of acetaminophen (glucuronide/sulphate) in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen, and to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in the key CYP enzymes (<i>CYP1A2*3</i>, <i>CYP1A2*4</i>, <i>CYP1A2*1C, CYP1A2*1K, CYP1A2*6</i>, <i>CYP2D6*10, CYP2E1*2</i>, <i>CYP2E1*5B, CYP3A4*1B, CYP3A4*2</i>, <i>CYP3A4*3</i>, <i>CYP3A5*3, CYP3A5*7,</i> and <i>CYP3A5*11</i>) and their effect on urinary metabolites and serum acetaminophen concentrations.Nineteen (32.8%) neonates had heterozygous <i>CYP1A2*1C</i>, two (3.3%) with heterozygous <i>CYP1A2*1K</i>, 15 (27.8%) and two (3.7%) had heterozygous and homozygous <i>CYP2D6*10</i>, two (3.7%) had heterozygous <i>CYP2E1*5B</i>, seven (12.3%) and three (5.3%) had heterozygous and homozygous <i>CYP3A4*1B</i>, and three (5.5%) had <i>CYP3A5*7</i> amongst the study population. Acetaminophen sulphate predominated over glucuronide metabolite at all time points. Postnatal days of life was significantly associated with an increase in the urine acetaminophen metabolites with decreased serum acetaminophen concentrations.A significant prevalence of SNPs in the key CYP enzymes related to acetaminophen metabolism was observed in our neonatal population. Population pharmacokinetic-pharmacodynamic modelling incorporating genetic and metabolite data is urgently needed for implementation of precision medicine in this vulnerable population. Acetaminophen is gaining importance as a first-line drug for treating patent ductus arteriosus (PDA) in neonates. Predominant metabolites of acetaminophen in preterm neonates vary from that of adults; and the drug is predominantly metabolised by conjugation and partly by Cytochrome P450 (CYP) enzymes. We carried out the present study to identify the principal urine metabolites of acetaminophen (glucuronide/sulphate) in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen, and to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in the key CYP enzymes (<i>CYP1A2*3</i>, <i>CYP1A2*4</i>, <i>CYP1A2*1C, CYP1A2*1K, CYP1A2*6</i>, <i>CYP2D6*10, CYP2E1*2</i>, <i>CYP2E1*5B, CYP3A4*1B, CYP3A4*2</i>, <i>CYP3A4*3</i>, <i>CYP3A5*3, CYP3A5*7,</i> and <i>CYP3A5*11</i>) and their effect on urinary metabolites and serum acetaminophen concentrations. Nineteen (32.8%) neonates had heterozygous <i>CYP1A2*1C</i>, two (3.3%) with heterozygous <i>CYP1A2*1K</i>, 15 (27.8%) and two (3.7%) had heterozygous and homozygous <i>CYP2D6*10</i>, two (3.7%) had heterozygous <i>CYP2E1*5B</i>, seven (12.3%) and three (5.3%) had heterozygous and homozygous <i>CYP3A4*1B</i>, and three (5.5%) had <i>CYP3A5*7</i> amongst the study population. Acetaminophen sulphate predominated over glucuronide metabolite at all time points. Postnatal days of life was significantly associated with an increase in the urine acetaminophen metabolites with decreased serum acetaminophen concentrations. A significant prevalence of SNPs in the key CYP enzymes related to acetaminophen metabolism was observed in our neonatal population. Population pharmacokinetic-pharmacodynamic modelling incorporating genetic and metabolite data is urgently needed for implementation of precision medicine in this vulnerable population.