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Relationship between the pharmacokinetics and iron excretion pharmacodynamics of the new oral iron chelator 1,2‐dimethyl‐3‐hydroxypyrid‐4‐one in patients with thalassemia
Author(s) -
Matsui Doreen,
Klein Julia,
Hermann Christine,
Grunau Victor,
McClelland Robert,
Chung Derrik,
StLouis Patrick,
Olivieri Nancy,
Koren Gideon
Publication year - 1991
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1991.139
Subject(s) - pharmacokinetics , excretion , pharmacodynamics , pharmacology , chemistry , renal physiology , volunteer , chelation therapy , absorption (acoustics) , oral administration , thalassemia , medicine , kidney , biochemistry , biology , agronomy , physics , acoustics
Single‐dose and steady‐state pharmacokinetics of the new oral iron chelator, l,2‐dimethyl‐3‐hydroxy‐pyrid‐4‐one (LI) were studied in 14 patients with thalassemia and correlated with iron excretion. Food prolongs the rate of absorption of LI, but it does not affect significantly the extent of absorption measured by the area under the plasma concentration–time curve. Similarly, it does not affect the chelation potential of the drug. The mean elimination half‐life of the drug is 3 hours, suggesting that a divided dose every 8 hours may assure better chelation. Our steady‐state studies reveal that urinary iron excretion is independently influenced by body iron load (measured by ferritin levels) and by steady‐state trough concentrations of the drug. While patients were receiving an unchanged regimen of 75 mg/kg/day, we have detected a gradual and significant decrease in trough concentrations in the presence of unchanged patients' compliance monitored by the Medication Event Monitoring System, diaries, and pill count. These findings suggest self‐induction of LI metabolism or decreased absorption during long‐term therapy. Because of the concentration‐dependent iron excretion, patients may need increasing doses to achieve negative iron balance. Clinical Pharmacology and Therapeutics (1991) 50, 294–298; doi: 10.1038/clpt.1991.139