RT Journal Article
SR Electronic
T1 In Vitro Cytochrome P450 Activity Decreases in Children with High Pediatric End-Stage Liver Disease Scores
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 390
OP 397
DO 10.1124/dmd.112.048504
VO 41
IS 2
A1 Lies De Bock
A1 Koen Boussery
A1 Myriam Van Winckel
A1 Peter De Paepe
A1 Xavier Rogiers
A1 Xavier Stephenne
A1 Etienne Sokal
A1 Jan Van Bocxlaer
YR 2013
UL http://dmd.aspetjournals.org/content/41/2/390.abstract
AB To improve the modeling and simulation of pharmacokinetics in pediatric patients, research into developmental and disease-specific determinants is needed. This article describes the evaluation of the activity of in vitro cytochrome P450 (P450), an important enzyme family in drug metabolism, in children with hepatic dysfunction. The activity of six P450 isoforms (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) was evaluated in 31 patients with different pathologies, predominantly biliary atresia (n = 23). Hypervariable activity was observed for all the isoforms. Compared with average adult activity, low activity levels were seen for CYP1A2, 2C19, 2E1, and 3A4. For CYP2E1 and 3A4, a positive correlation between activity and abundance was observed. Age, comedication, and genotype could not be used as predictors for P450 activity in this patient population. In contrast, the pediatric end-stage liver disease score was negatively correlated with the ln(activity). This finding suggests a decrease in P450 activity with deteriorating hepatic function. Moreover, the activity of all isoforms was correlated, demonstrating a concomitant decrease of all isoforms in young patients with liver disease. To our knowledge, this is the first study to evaluate P450 activity in children with hepatic impairment. The presented data may provide support in the further optimization of a disease-specific model in this patient population.