Keliang Wu, Jianye Wang 6, Wenhui Du 1, Karel Allegaert 3,4,5, Wei Zhao 1,2
1 Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine (Jinan, China), 2 NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Shandong University (Jinan, China), 3 Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences (3000 Leuven, Belgium), 4 Department of Development and Regeneration (3000 Leuven, Belgium), 5 Department of Hospital Pharmacy, Erasmus University Medical Center (3000 CA Rotterdam, The Netherlands), 6 Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University (Jinan, China)
Introduction：
Age-related maturation of drug transport and metabolic pathways governs pediatric drug disposition and underpins model-informed extrapolation across developmental stages [1-4]. Comprehensive ontogeny profiles describing these pathways in the intestine have been established primarily in Caucasian populations [2]. However, evidence supporting the direct transferability of these ontogeny patterns across ethnicities remains limited. This gap underscores the need for ethnicity-specific characterization of developmental expression patterns to support more accurate pediatric dose optimization.
Objective：
To characterize age-dependent expression of key intestinal drug transporters (DT) and drug metabolizing enzymes (DE) in Chinese population using a targeted quantitative proteomic approach, to define developmental trajectories at both protein and transcript levels, and to compare these ontogeny patterns with published Caucasian data[2] to assess potential ethnic differences.
Method：
Human small intestinal tissues (n = 75; age 0.01–58 years) from Chinese donors were included to cover the full developmental spectrum from neonates to adults. This study was approved by the Shandong Province Hospital Ethics Committee, and written informed consent was obtained from all participants or their legal guardians.
Absolute protein abundance of selected DT and DE was determined using a targeted LC–MS/MS-based quantitative proteomics platform, employing surrogate peptides for protein-specific quantification[5].
Transcript abundance was assessed using transcriptome-wide expression profiling.
To correct for differences in cellular composition within intestinal tissue samples, protein expression data were additionally normalized to villin-1 (VIL1), an established intestinal epithelial marker[6], thereby adjusting for variability in epithelial content[7]. Age-dependent expression trajectories were subsequently evaluated across developmental stages.
Result：
In the quantitative proteomic analysis, VIL1 and CYP3A5 were consistently detected across all samples. In contrast, CYP2C9 was not detected in any samples.
Age-dependent differences were observed across age groups in both protein abundance and mRNA expression of DT and DE.
For BCRP, protein abundance was lowest in the newborn and increased progressively across age groups, with significantly higher levels in the adult compared with pediatric age groups. At the mRNA level, expression was reduced in the newborn compared with infant and child. OATP2B1 protein abundance was higher in infant and child compared with the adult. CYP3A5 protein was detectable across all age groups and appeared lower in the adult compared with younger age groups. UGT1A1 demonstrated marked developmental differences across age groups at both protein and mRNA levels. Protein abundance was minimal in newborn and infant age groups and increased progressively toward adulthood, reaching the highest levels in the adult age group. Similarly, UGT1A1 mRNA expression was low in the newborn and significantly increased in infant and child. UGT1A10 mRNA expression showed low levels in early age groups and higher levels in later age groups. ASBT mRNA expression was lowest in the newborn and increased in infant and child, with significant differences between neonatal and later age groups. OCT1 mRNA expression was higher in early age groups compared with the adult. PEPT1 mRNA expression was detected across all age groups and demonstrated significant differences between selected age groups.
When compared with published Caucasian ontogeny data[2], both similar and distinct differences in patterns were observed. In the Chinese cohort, UGT1A1 protein abundance increased across age groups, with lowest levels in early age groups and higher levels in adulthood. A similar age-dependent increase was observed in published Caucasian data. BCRP protein abundance showed age-related stratification in both cohorts. For PEPT1 and CYP3A5, age-dependent differences were observed in Caucasian populations, with higher expression levels in later age groups compared with early life. In the Chinese cohort, these proteins did not demonstrate a consistent monotonic increase across age groups. OATP2B1 protein abundance did not display a clear age-dependent trend in either cohort.
Conclusion：
This study delineates age-dependent expression patterns of multiple key intestinal DT and DE in Chinese population at both protein and transcript levels. Distinct maturation trajectories were observed across targets, including UGT1A1, BCRP, PEPT1, CYP3A5, and OATP2B1, with target-specific developmental profiles across age groups.
Cross-ethnic comparison further revealed that while certain enzymes demonstrated broadly consistent maturation patterns, several transporters exhibited ethnic specific developmental trajectories. These findings provide quantitative, ethnicity-specific ontogeny data that may improve the mechanistic basis of pediatric model extrapolation and support more precise, population-informed dose optimization.
Co-corresponding authors：Karel Allegaert, Wei Zhao
References:
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[6] Zhang, Haeyoung et al. “Regional Proteomic Quantification of Clinically Relevant Non-Cytochrome P450 Enzymes along the Human Small Intestine.” Drug metabolism and disposition: the biological fate of chemicals vol. 48,7 (2020): 528-536.
[7] West, A B et al. “Localization of villin, a cytoskeletal protein specific to microvilli, in human ileum and colon and in colonic neoplasms.” Gastroenterology vol. 94,2 (1988): 343-52.
Reference: PAGE 34 (2026) Abstr 11914 [www.page-meeting.org/?abstract=11914]
Poster: Drug/Disease Modelling - Other Topics