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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
Summary
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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