Pharmacokinetic-Pharmacodynamic Modeling of Manganese After a Single Intravenous Infusion of Mangafodipir in Patients With Acute Alcoholic Hepatitis
| Autor: | Saïk Urien, Jean-Marc Tréluyer, Déborah Hirt, Silvana Pavlovic, Jean-Philippe Richardet, Bernard Weill, Frédéric Batteux, Alexis Laurent, Joël Poupon, Philippe Sogni, Marcel Debray |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Adult
Male medicine.medical_specialty Pathology Adolescent Metabolic Clearance Rate Bilirubin Population Alcoholic hepatitis Drug Administration Schedule Young Adult chemistry.chemical_compound Pharmacokinetics Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Mangafodipir Humans Drug Interactions Pharmacology (medical) Anesthetics Local Infusions Intravenous education Edetic Acid Aged Etoposide Pharmacology Prothrombin time Volume of distribution Manganese education.field_of_study medicine.diagnostic_test Hepatitis Alcoholic business.industry Middle Aged medicine.disease Endocrinology chemistry Vincristine Pyridoxal Phosphate Pharmacodynamics Acute Disease Prednisone Mitoxantrone business medicine.drug |
| Zdroj: | ResearcherID |
| ISSN: | 0163-4356 |
| DOI: | 10.1097/ftd.0b013e3181affd6d |
| Popis: | To determine the pharmacokinetic (PK) profile of manganese (Mn) after a 2-hour intravenous infusion of mangafodipir at 5 micromol/kg body weight and to correlate Mn concentrations with oxidative stress, early decrease in serum total bilirubin concentration, and prothrombin time (PT) in chronic alcoholic patients with acute alcoholic hepatitis. In 7 patients, a total of 49 serum Mn concentrations were determined on day 1 (before the start of the infusion and 15, 30, and 45 minutes after the end of the infusion) and on days 2, 7, 14, and 21. Fifty-seven PTs, reflecting liver activity, were measured on days 1, 2, 7, 14, and 21 and at months 1, 2, and 3. A population PK-pharmacodynamic model was developed to describe the kinetics of serum Mn concentrations and PT, to estimate interpatient variability, and to test covariate influence. A 2-compartment model with zero-order absorption and first-order elimination best described the data, and a signal transduction model with 2 transit compartments best described PT. Mean PK estimates and the corresponding interindividual variabilities (%) were clearance 23.1 L/h (34%), central and peripheral volume of distribution 35.4 and 1090 L, respectively, intercompartmental clearance 27.3 L (34%), endogenous Mn concentrations 15.8 nmol/L, slope-relating effect to concentration 141 nmol x L(-1) x s(-1) (52%), and mean transit time (tau) 3.8 days (34%). When patients had an early decrease in bilirubin at day 7, tau increased to 28.2 days. Serum Mn concentrations could be related to a decrease in PT; the effect was longer in patients with an early decrease in total bilirubin serum concentrations. |
| Databáze: | OpenAIRE |
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