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Characterization of Atomoxetine Biotransformation and Implications for Development of PBPK Models for Dose Individualization in Children.
Dinh, Jean C; Pearce, Robin E; Van Haandel, Leon; Gaedigk, Andrea; Leeder, J Steven.
Afiliação
  • Dinh JC; Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation (J.C.D., L.V.H., R.E.P., A.G., J.S.L.), Department of Pediatrics, Children's Mercy Hospital (L.V.H., R.E.P., A.G., J.S.L.), University of Kansas Medical Center (J.S.L.), and Department of Pharmacology (A.G., R.E.P., J.S.L.), U
  • Pearce RE; Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation (J.C.D., L.V.H., R.E.P., A.G., J.S.L.), Department of Pediatrics, Children's Mercy Hospital (L.V.H., R.E.P., A.G., J.S.L.), University of Kansas Medical Center (J.S.L.), and Department of Pharmacology (A.G., R.E.P., J.S.L.), U
  • Van Haandel L; Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation (J.C.D., L.V.H., R.E.P., A.G., J.S.L.), Department of Pediatrics, Children's Mercy Hospital (L.V.H., R.E.P., A.G., J.S.L.), University of Kansas Medical Center (J.S.L.), and Department of Pharmacology (A.G., R.E.P., J.S.L.), U
  • Gaedigk A; Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation (J.C.D., L.V.H., R.E.P., A.G., J.S.L.), Department of Pediatrics, Children's Mercy Hospital (L.V.H., R.E.P., A.G., J.S.L.), University of Kansas Medical Center (J.S.L.), and Department of Pharmacology (A.G., R.E.P., J.S.L.), U
  • Leeder JS; Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation (J.C.D., L.V.H., R.E.P., A.G., J.S.L.), Department of Pediatrics, Children's Mercy Hospital (L.V.H., R.E.P., A.G., J.S.L.), University of Kansas Medical Center (J.S.L.), and Department of Pharmacology (A.G., R.E.P., J.S.L.), U
Drug Metab Dispos ; 44(7): 1070-9, 2016 07.
Article em En | MEDLINE | ID: mdl-27052878
Atomoxetine (ATX) is a second-line nonstimulant medication used to control symptoms of attention deficit hyperactivity disorder (ADHD). Inconsistent therapeutic efficacy has been reported with ATX, which may be related to variable CYP2D6-mediated drug clearance. We characterized ATX metabolism in a panel of human liver samples as a basis for a bottom-up PBPK model to aid in ATX exposure prediction and control. Km, Vmax, and Clint values in pooled human liver microsomes (HLMs) were 2.4 µM, 479 pmol/min/mg protein, and 202 µl/min/mg protein, respectively. Mean population values of kinetic parameters are not adequate to describe variability in a population, given that Km, Vmax, and Clint values from single-donor HLMs ranged from 0.93 to 79.2 µM, 20.0 to 1600 pmol/min/mg protein, and 0.3 to 936 µl/min/mg protein. All kinetic parameters were calculated from 4-hydroxyatomoxetine (4-OH-ATX) formation. CYP2E1 and CYP3A contributed to 4-OH-ATX formation in livers with CYP2D6 intermediate and poor metabolizer status. In HLMs with lower CYP2D6 activity levels, 2-hydroxymethylatomoxetine (2-CH2OH-ATX) formation became a more predominant pathway of metabolism, which appeared to be catalyzed by CYP2B6. ATX biotransformation at clinically relevant plasma concentrations was characterized in a panel of pediatric HLM (n = 116) samples by evaluating primary metabolites. Competing pathways of ATX metabolism [N-desmethylatomoxetine (NDM-ATX) and 2-CH2OH-ATX formation] had increasing importance in livers with lesser CYP2D6 activity, but, overall ATX clearance was still compromised. Modeling ATX exposure to individualize therapy would require comprehensive knowledge of factors that affect CYP2D6 activity as well as an understanding of competing pathways, particularly for individuals with lower CYP2D6 activity.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtorno do Deficit de Atenção com Hiperatividade / Sistema Enzimático do Citocromo P-450 / Cálculos da Dosagem de Medicamento / Cloridrato de Atomoxetina / Estimulantes do Sistema Nervoso Central / Modelos Biológicos Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Adolescent / Adult / Child / Humans / Infant / Middle aged Idioma: En Revista: Drug Metab Dispos Assunto da revista: FARMACOLOGIA Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtorno do Deficit de Atenção com Hiperatividade / Sistema Enzimático do Citocromo P-450 / Cálculos da Dosagem de Medicamento / Cloridrato de Atomoxetina / Estimulantes do Sistema Nervoso Central / Modelos Biológicos Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Adolescent / Adult / Child / Humans / Infant / Middle aged Idioma: En Revista: Drug Metab Dispos Assunto da revista: FARMACOLOGIA Ano de publicação: 2016 Tipo de documento: Article