title: Pharmacokinetic-pharmacodynamic modeling of manganese after a single intravenous infusion of mangafodipir in patients with acute alcoholic hepatitis.
abstract: 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.
authors.affiliation: EA3620, Université Paris-Descartes, Paris, France. deborah.hirt@univ-paris5.fr
authors.forename: Déborah
authors.initials: D
authors.lastname: Hirt
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Richardet
authors.forename: Saïk
authors.initials: S
authors.lastname: Urien
authors.forename: Joël
authors.initials: J
authors.lastname: Poupon
authors.forename: Philippe
authors.initials: P
authors.lastname: Sogni
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.forename: Alexis
authors.initials: A
authors.lastname: Laurent
authors.forename: Silvana
authors.initials: S
authors.lastname: Pavlovic
authors.forename: Marcel
authors.initials: M
authors.lastname: Debray
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Treluyer
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004492:Edetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005047:Etoposide; D006519:Hepatitis, Alcoholic / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008345:Manganese / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008942:Mitoxantrone; D011241:Prednisone; D011732:Pyridoxal Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014750:Vincristine; D055815:Young Adult
chemical_list: D000779:Anesthetics, Local; D008345:Manganese; D014750:Vincristine; D011732:Pyridoxal Phosphate; D005047:Etoposide; D004492:Edetic Acid; D008942:Mitoxantrone; C060076:N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid; D011241:Prednisone