C Gade1, K Dalhoff1, T S Petersen1, T Riis1, C Schmeltz2, E Chabanova3, H R Christensen1, G Mikus4, J Burhenne4, J C Holm5,6,7, H Holst1. 1. Department of Clinical Pharmacology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark. 2. Children's Obesity Clinic, European Center of Management (EASO). Department of Pediatrics, Zealand University Hospital, Holbaek, Denmark. 3. Faculty of Health and Medical Sciences, Copenhagen University, Department of Radiology, Herlev and Gentofte Hospital, Denmark. 4. Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Germany. 5. The Children's Obesity Clinic, Department of Paediatrics, Copenhagen University Hospital Holbaek, Denmark. 6. Novo Nordisk Foundation Centre for Basic Metabolic Research, Denmark. 7. Department of Clinical Medicine, University of Copenhagen, Denmark.
Abstract
AIMS: To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obese children vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS: Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS: Obese children had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-∞ value of CLZ was decreased by 46% in obese children compared to nonobese children. The F was was increased twofold in obese children compared to nonobese children, P < 0.0001. Diabetic biomarkers were significantly increased in obese children, while fasting blood glucose and Hba1c levels were nonsignificant between groups. Liver fat content was not associated with CLZ Cl. CONCLUSION: Oral clearance of CLZ was increased two-fold in obese children vs. nonobese children aged 11-18 years. This indicates an increased CYP2E1 activity of clinical importance, and dose adjustment should be considered for CLZ.
AIMS: To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obesechildren vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS: Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS:Obesechildren had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-∞ value of CLZ was decreased by 46% in obesechildren compared to nonobese children. The F was was increased twofold in obesechildren compared to nonobese children, P < 0.0001. Diabetic biomarkers were significantly increased in obesechildren, while fasting blood glucose and Hba1c levels were nonsignificant between groups. Liver fat content was not associated with CLZ Cl. CONCLUSION: Oral clearance of CLZ was increased two-fold in obesechildren vs. nonobese children aged 11-18 years. This indicates an increased CYP2E1 activity of clinical importance, and dose adjustment should be considered for CLZ.
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