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Unveiling Hepatic Protein Alterations in Neonatal and Infant Biliary Atresia

Zubida M Al-Majdoub1, Martyn Howard1, Brahim Achour2

  • 1Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester, Manchester, UK.

Clinical Pharmacology and Therapeutics
|March 4, 2026
PubMed

Insights

Biliary atresia (BA) significantly alters drug-metabolizing enzymes and transporters in infants, impacting drug clearance. This highlights the need for pediatric pharmacokinetic studies in BA patients to ensure safe and effective dosing.

Area of Science:

  • Pharmacology
  • Hepatology
  • Pediatric Medicine

Background:

  • Pediatric drug elimination differs from adults due to developmental changes.
  • Biliary atresia (BA), a neonatal liver disease, can impair hepatic drug clearance, necessitating dose adjustments.
  • Current methods for pediatric drug dosing often overlook comorbidities like BA, leading to potential inaccuracies.

Purpose of the Study:

  • To investigate the impact of biliary atresia on the expression of drug-metabolizing enzymes and transporters in pediatric liver samples.
  • To provide quantitative proteomic data for developing physiologically based pharmacokinetic (PBPK) models in BA patients.
  • To underscore the need for clinical pharmacokinetic studies in BA to guide precision dosing.

Main Methods:

  • Global liquid chromatography and tandem mass spectrometry (LC-MS/MS) proteomics were employed.
  • Drug-metabolizing enzymes and transporters were quantified in neonatal and infant liver samples from BA patients and controls.
  • Expression levels were compared between BA and control cohorts.

Main Results:

  • Significant alterations in enzyme and transporter expression were observed in BA livers compared to controls.
  • CYP2A6, CYP2B6, and CYP2E1 levels were markedly higher (6-17-fold) in BA livers, while CYP4F11 and CYP20A1 were reduced.
  • UGT enzymes (UGT1A1, UGT2B4, UGT2B7) showed increased abundance (up to 16-fold) in neonates with BA, and ABCF1 transporter increased dramatically (46-fold).
  • Several transporters, including B3AT/SLC4A1, ADT1/SLC25A4, and S27A5/SLC27A5, showed decreased abundance.

Conclusions:

  • Biliary atresia profoundly impacts hepatic drug clearance pathways by altering enzyme and transporter expression.
  • Assuming similar liver function in BA and non-BA pediatric patients can lead to inappropriate drug dosing.
  • Urgent, dedicated pharmacokinetic studies in BA patients are essential for improving precision dosing and patient outcomes.

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