In Vitro Cytochrome P450 Activity Decreases in Children with High Pediatric End-Stage Liver Disease Scores

Abstract

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 diseasespecific model in this patient population.

Correspondence between the CYP2C19 and CYP3A4 genotypes with the inferred metabolizer phenotype by omeprazole administration in Mexican healthy children

“…The minor effect of the elapsed time after drug administration can be explained because HI and SI change simultaneously; thus, this index is constant during the presence of the drug in the body . This explanation is consistent with the significant correlation estimated between OME/HOME and OME/SOME plasma concentrations ( r 2 = .4217, P < .0001) (Appendix S2), as previously described . In brief, our results suggest that sampling time variations after OME administration for CYP2C19 and CYP3A4 phenotyping purposes are damped by the parallel relationship between OME, HOME and SOME, and by the sensitivity of the HPLC quantification technique (subsection 2.4).…”

“…These histograms displayed a similar HI and SI distribution between subgroups ( P > .05), suggesting a minor impact of these variables. The minor effect of the elapsed time after drug administration can be explained because HI and SI change simultaneously; thus, this index is constant during the presence of the drug in the body . This explanation is consistent with the significant correlation estimated between OME/HOME and OME/SOME plasma concentrations ( r 2 = .4217, P < .0001) (Appendix S2), as previously described .…”

“…[2][3][4]15 After CYP2C19 and CYP3A4 phenotyping, individuals were classified as UM, EM and PM for CYP2C19 and CYP3A4 based upon the HI and SI, respectively (Appendix S1a-f). However, due to the variation in 26,27 This explanation is consistent with the significant correlation estimated between OME/HOME and OME/ SOME plasma concentrations (r 2 = .4217, P < .0001) (Appendix S2), as previously described. 27 In brief, our results suggest that sampling time variations after OME administration for CYP2C19 and CYP3A4 phenotyping purposes are damped by the parallel relationship between OME, HOME and SOME, and by the sensitivity of the HPLC quantification technique (subsection 2.4).…”

Microsomal protein per gram of liver (MPPGL) in paediatric biliary atresia patients

“…In accordance to the incubation experiments previously performed in this study , on the one hand pools were made based on the amount of liver, in order to rule out possible zonal differences. As seen in Table , low recovery factors were seen for some samples, probably due to the cirrhotic nature of the samples and the consequent longer and stronger homogenization needed.…”

Activity of cytochrome P450 1A2 in relation to hepatic iron accumulation in transfusion‐dependent β‐thalassaemia major patients

“…Cytochrome P450 1A2 function was previously reported as a marker for decreased liver function in hepatitis C and children with end‐stage liver disease . It was rather surprising that in patients in which iron load was high, CYP1A2 function was normal, suggesting normal liver function.…”