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In vitro cytochrome P450 activity decreases in children with high paediatric end-stage liver disease scores

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Abstract
To improve modelling and simulation of the pharmacokinetics (PK) in paediatric patients, there is a need for research on developmental and disease-specific determinants. This article describes the evaluation of the in vitro cytochrome P450 activity, an important enzyme family in drug metabolism, in children with hepatic dysfunction. The activity of 6 CYP isoforms, CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 was evaluated in thirty-one patients with different pathologies, mainly biliary atresia (n=23). A hypervariable activity was observed for all the isoforms. Compared to an average adult activity, low activities were seen for CYP1A2, 2C19, 2E1, and 3A4. For CYP2E1 and 3A4, a positive correlation between activity and abundance was observed. In this population, age, co-medication, and genotype could not be used as predictors for the CYP activity. In contrast, the Paediatric End-stage Liver Disease score was negatively correlated with the ln(activity). This suggests a decrease in CYP 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 CYP 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.
Keywords
DRUG-METABOLIZING-ENZYMES, CURRENT SITUATION, PHARMACOKINETICS, TRANSPLANTATION, CLEARANCE, ONTOGENY, QUANTIFICATION, VALIDATION, OMEPRAZOLE, CIRRHOSIS

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Chicago
De Bock, Lies, Koen Boussery, Myriam Van Winckel, Peter De Paepe, Xavier Rogiers, Xavier Stephenne, Etienne Sokal, and Jan Van Bocxlaer. 2013. “In Vitro Cytochrome P450 Activity Decreases in Children with High Paediatric End-stage Liver Disease Scores.” Drug Metabolism and Disposition 41 (2): 390–397.
APA
De Bock, Lies, Boussery, K., Van Winckel, M., De Paepe, P., Rogiers, X., Stephenne, X., Sokal, E., et al. (2013). In vitro cytochrome P450 activity decreases in children with high paediatric end-stage liver disease scores. DRUG METABOLISM AND DISPOSITION, 41(2), 390–397.
Vancouver
1.
De Bock L, Boussery K, Van Winckel M, De Paepe P, Rogiers X, Stephenne X, et al. In vitro cytochrome P450 activity decreases in children with high paediatric end-stage liver disease scores. DRUG METABOLISM AND DISPOSITION. 2013;41(2):390–7.
MLA
De Bock, Lies, Koen Boussery, Myriam Van Winckel, et al. “In Vitro Cytochrome P450 Activity Decreases in Children with High Paediatric End-stage Liver Disease Scores.” DRUG METABOLISM AND DISPOSITION 41.2 (2013): 390–397. Print.
@article{3054682,
  abstract     = {To improve modelling and simulation of the pharmacokinetics (PK) in paediatric patients, there is a need for research on developmental and disease-specific determinants. This article describes the evaluation of the in vitro cytochrome P450 activity, an important enzyme family in drug metabolism, in children with hepatic dysfunction. The activity of 6 CYP isoforms, CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 was evaluated in thirty-one patients with different pathologies, mainly biliary atresia (n=23). A hypervariable activity was observed for all the isoforms. Compared to an average adult activity, low activities were seen for CYP1A2, 2C19, 2E1, and 3A4. For CYP2E1 and 3A4, a positive correlation between activity and abundance was observed. In this population, age, co-medication, and genotype could not be used as predictors for the CYP activity. In contrast, the Paediatric End-stage Liver Disease score was negatively correlated with the ln(activity). This suggests a decrease in CYP 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 CYP 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.},
  author       = {De Bock, Lies and Boussery, Koen and Van Winckel, Myriam and De Paepe, Peter and Rogiers, Xavier and Stephenne, Xavier and Sokal, Etienne and Van Bocxlaer, Jan},
  issn         = {0090-9556},
  journal      = {DRUG METABOLISM AND DISPOSITION},
  language     = {eng},
  number       = {2},
  pages        = {390--397},
  title        = {In vitro cytochrome P450 activity decreases in children with high paediatric end-stage liver disease scores},
  url          = {http://dx.doi.org/10.1124/dmd.112.048504},
  volume       = {41},
  year         = {2013},
}

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