Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites

Chalon, Stephan; Desager, Jean‐Pierre; DeSante, Karl A.; Frye, Reginald F.; Witcher, Jennifer; Long, Amanda; Sauer, John‐Michael; Golnez, Jean-Luc; Smith, Brian P.; Thomasson, Holly R.; Horsmans, Yves

doi:10.1067/mcp.2003.25

Cited by 61 publications

(34 citation statements)

References 27 publications

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“…The expression of drug disposition genes and their protein products has been shown to be altered in liver disease (Congiu et al, 2002(Congiu et al, , 2009Fisher et al, 2009), and effects of liver disease on the disposition of drugs have been demonstrated and tend to be more severe in patients with more advanced cirrhotic disease (Chalon et al, 2003). In contrast, significant differences in the disposition of drugs between different types of liver disease have not been demonstrated.…”

Section: Discussionmentioning

confidence: 83%

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

Schrieber¹,

Hawke²,

Zhao³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single-and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC 0-8 h ) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC 0-8 h was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC 0-8 h (p < 0.05) and 42% lower C max (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients.

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Section: Discussionmentioning

confidence: 83%

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

Schrieber¹,

Hawke²,

Zhao³

et al. 2011

Drug Metab Dispos

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“…Polymorphic hepatic cytochrome P4502D6 plays an important role in the the metabolism of atomoxetine. Patients with a "poor metabolizer" phenotype have been shown to have a prolonged plasma elimination half-life (1,2). Pharmacokinetics in overdose, and how they may be influenced by polymorphic expression of CYP2D6, is unknown at this time.…”

Section: Discussionmentioning

confidence: 98%

“…It is a specific norepinephrine reuptake inhibitor that has no direct effect on other neurotransmitter systems (2). Atomoxetine is marketed as a non-stimulant alternative in the treatment of ADHD.…”

Section: Introductionmentioning

confidence: 99%

Isolated atomoxetine overdose resulting in seizure

Kashani

Ruha

2007

The Journal of Emergency Medicine

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“…Dementsprechend ist bei Patienten mit einer moderaten oder schweren Leberfunktionsstörung eine entsprechende Dosisanpassung erforderlich, bei Patienten mit Nierenfunktionsstörungen kann Atomoxetin hingegen in normaler Dosis weiter verabreicht werden. Die pharmakokinetischen Eigenschaften von Atomoxetin wurden bisher nicht bei Kindern unter 6 Jahren und bei geriatrischen Patienten untersucht [13,18,19,29].…”

Section: Pharmakokinetik Und Metabolismusunclassified

Atomoxetin in der Behandlung der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Kindern und Erwachsenen

Davids

Gastpar²

2004

Fortschr Neurol Psychiatr

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Atomoxetine is a selective noradrenaline reuptake inhibitor that has been studied for use in the treatment of attention-deficit/hyperactivity disorder (ADHD). In vitro, ex vivo and in vivo studies have shown that atomoxetine is a highly selective antagonist of the presynaptic norepinephrine transporter with little or no affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. So far, two open-label and seven randomised, double-blind, placebo-controlled, clinical trials have been published, six in youths and three in adults. Each of these trials has shown a positive response as measured by the primary efficacy measures, the ADHD-IV Rating Scale (ADHD RS) or the Conners Adult ADHD Rating Scale (CAARS). Atomoxetine has generally been well tolerated. The most common treatment-related adverse event was decreased appetite. Atomoxetine shows no abuse potential and is not a controlled substance in the US. In November of 2002 the FDA approved atomoxetine for use in the US for the treatment of ADHD in children, adolescents and adults. Atomoxetine is the first nonstimulant approved by the FDA for the treatment of ADHD and the first medication approved for the treatment of adult ADHD.

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Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites

Abstract: For patients with attention-deficit/hyperactivity disorder who have hepatic impairment, dosage adjustment is recommended. Initial target doses should be reduced to 25% and 50% of the normal dose for patients with severe and moderate hepatic impairment, respectively.

Cited by 61 publications

References 27 publications

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

Isolated atomoxetine overdose resulting in seizure

Atomoxetin in der Behandlung der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Kindern und Erwachsenen

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