Pediatric cytochrome P450 activity alterations in nonalcoholic steatohepatitis

Hui Li, Mark J. Canet, John D. Clarke, David D Billheimer, Stavra A. Xanthakos, Joel E. Lavine, Robert P. Erickson, Nathan J Cherrington

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Variable drug responses depend on individual variation in the activity of drug-metabolizing enzymes, including cytochrome P450 enzymes (CYP). As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis (NASH) has been identified as a source of significant interindividual variation in hepatic drug metabolism. Compared with adults, children present age-related differences in pharmacokinetics and pharmacodynamics. The purpose of this study was to determine the impact of fatty liver disease severity on the activity of a variety of CYP enzymes in children and adolescents. Healthy and nonalcoholic fatty liver disease pediatric subjects aged 12–21 years inclusive received an oral cocktail of four probe drugs: caffeine (CYP1A2, 100 mg), omeprazole (CYP2C19, 20 mg), losartan (CYP2C9, 25 mg), and midazolam (CYP3A4, 2 mg). Venous blood and urine were collected before administration and 1, 2, 4, and 6 hours after administration. Concentrations of the parent drugs and CYP-specific metabolites were quantified in plasma and urine using liquid chromatography with tandem mass spectrometry. In plasma, the decreased metabolic area under the curve (AUC) ratio, defined as the metabolite AUC to parent AUC, of omeprazole indicated significant decreases of CYP2C19 (P = 0.002) enzymatic activities in NASH adolescents, while the urine analyses did not show significant differences and were highly variable. A comparison between the present in vivo pediatric studies and a previous ex vivo study in adults indicates distinct differences in the activities of CYP1A2 and CYP2C9. These data demonstrate that pediatric NASH presents an altered pattern of CYP activity and NASH should be considered as a confounder of drug metabolism for certain CYP enzymes. These differences could lead to future investigations that may reveal unexpected variable drug responses that should be considered in pediatric dosage recommendations.

Original languageEnglish (US)
Pages (from-to)1317-1325
Number of pages9
JournalDrug Metabolism and Disposition
Volume45
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Cytochrome P-450 Enzyme System
Pediatrics
Pharmaceutical Preparations
Area Under Curve
Cytochrome P-450 CYP1A2
Omeprazole
Urine
Liver Diseases
Enzymes
Non-alcoholic Fatty Liver Disease
Cytochrome P-450 CYP3A
Losartan
Midazolam
Fatty Liver
Tandem Mass Spectrometry
Caffeine
Liquid Chromatography
Chronic Disease
Pharmacokinetics
Parents

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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Pediatric cytochrome P450 activity alterations in nonalcoholic steatohepatitis. / Li, Hui; Canet, Mark J.; Clarke, John D.; Billheimer, David D; Xanthakos, Stavra A.; Lavine, Joel E.; Erickson, Robert P.; Cherrington, Nathan J.

In: Drug Metabolism and Disposition, Vol. 45, No. 12, 01.12.2017, p. 1317-1325.

Research output: Contribution to journalArticle

Li, Hui ; Canet, Mark J. ; Clarke, John D. ; Billheimer, David D ; Xanthakos, Stavra A. ; Lavine, Joel E. ; Erickson, Robert P. ; Cherrington, Nathan J. / Pediatric cytochrome P450 activity alterations in nonalcoholic steatohepatitis. In: Drug Metabolism and Disposition. 2017 ; Vol. 45, No. 12. pp. 1317-1325.
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