الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
This dissertation is composed of two studies: the first is the proteomics study, which was performed using pig liver and pediatric postmortem human liver samples, while the second study was carried out on ALL pediatric patients. Age can cause considerable variation in the abundance of drug metabolizing enzymes and drug transporters in the pediatric population. These abundance levels are required to be fed into PBPK models. These models can be used to assist in the extrapolation of in vitro data to predict the in vivo behavior of drugs in any age group, including pediatrics. The proteomics study was performed between June 2016 and January 2017 at the University of Manchester, where two pig liver samples and 19 pediatric postmortem human liver samples were processed by different sample preparation protocols for the identification and quantification of drug metabolizing enzymes and drug transporters. The data obtained from the proteomics study showed different abundance levels for each identified drug metabolizing enzyme or drug transporter among different pediatric age groups, with a unique ontogeny profile for each protein. ALL pediatric patients (ALL group) (n = 33) received the standard treatment of HDMTX (dose: 2–5 gm/cm2), while the Healthy pediatric subjects did not receive any treatment and were selected from a primary care center of matched ages to the ALL group subjects. P-gp serum level was determined for the ALL group at baseline and after MTX treatment to evaluate the effects of MTX on P-gp serum level, and it was determined for the healthy group subjects as well. MTX concentration was measured for the ALL group after 42 hours of treatment to correlate with P-gp serum level. The data obtained from the ALL study showed that there was no statistically significant difference observed in P-gp serum level between the healthy pediatric subjects and the ALL patients before receiving MTX treatment, while P-gp serum level was significantly lower in pediatric patients with ALL after MTX treatment in all the pediatric age segments compared to its level before MTX treatment. Moreover, there was no statistically significant difference in P-gp serum level between the healthy pediatric subjects and pediatric patients with ALL after MTX treatment in the first age segments (4– 7 years old). However, P-gp serum level was significantly lower in pediatric patients with ALL who received MTX in both (8–10 years old) and (11–14 years old) age segments compared to the healthy group. There was no significant correlation between MTX concentration and P-gp serum level in the ALL patients after MTX treatment in the three age segments.