Document Detail


Pharmacokinetics of deferiprone in patients with β-thalassaemia: impact of splenectomy and iron status.
MedLine Citation:
PMID:  21028920     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND OBJECTIVE: Iron-rich transfusions and/or a compensatory increase in iron absorption ultimately result in iron loading in patients with β-thalassaemia. Hence, without iron chelation, iron accumulates relentlessly. Deferiprone has been shown to be capable of reducing the iron burden in patients with β-thalassaemia. However, there is wide interpatient variation in deferiprone-induced urinary iron excretion (UIE). We hypothesized that splenectomy and iron status might influence the pharmacokinetic profiles of deferiprone in patients with β-thalassaemia/haemoglobin E, and the present study was aimed at examining this hypothesis.
STUDY PARTICIPANTS AND METHODS: Thirty-one patients with β-thalassaemia/haemoglobin E (20 splenectomized and 11 non-splenectomized patients) were enrolled in the study. After an overnight fast, the subjects received a single oral dose of deferiprone 25 mg/kg of bodyweight. Blood samples were collected pre-dosing and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 480 minutes after dosing. Urine output was pooled and collected at 0-2, 2-4, 4-8, 8-12 and 12-24 hour intervals. Serum and urine concentrations of deferiprone and its metabolite deferiprone glucuronide were determined using a validated high-performance liquid chromatography method. Serum deferiprone-chelated iron and UIE were determined using a validated colourimetric method.
RESULTS: No significant difference in the pharmacokinetic parameters of non-conjugated deferiprone was observed between splenectomized and non-splenectomized patients. However, the maximum serum concentration (C(max)) and the area under the serum concentration-time curve (AUC) from time zero to infinity (AUC(∞)) values of deferiprone glucuronide were significantly lower (both p < 0.05) in splenectomized patients (median 53.2 μmol/L and 12 634 μmol • min/L, respectively) than in non-splenectomized patients (median 70.5 μmol/L and 20 601 μmol • min/L, respectively). The C(max) and the AUC from time zero to the time of the last measurable concentration (AUC(last)) values of serum deferiprone-chelated iron, as well as UIE, were significantly higher (p < 0.001) in splenectomized patients (median values 7.1 μmol/L, 1645 μmol • min/L and 77.1 μmol, respectively) than in non-splenectomized patients (median values 3.1 μmol/L, 545 μmol • min/L and 12.5 μmol, respectively). Urinary excretion of non-conjugated deferiprone and deferiprone glucuronide did not differ between the two groups. Further analyses using multiple linear regressions indicated that the iron profiles (non-transferrin-bound iron and ferritin) were significant predictors of the pharmacokinetic parameters of non-conjugated deferiprone, deferiprone-chelated iron and UIE. In addition, splenectomy status was identified as the strongest predictor of the AUC(last) of deferiprone-chelated iron and UIE.
CONCLUSION: Both iron and splenectomy status have significant effects on the pharmacokinetics and iron chelation efficacy of deferiprone. A greater degree of iron overload in splenectomized patients results in alterations in pharmacokinetic parameters (the C(max) and AUC) of deferiprone glucuronide and deferiprone-chelated iron, as well as a significant increase in UIE.
Authors:
Lie Michael George Limenta; Totsapol Jirasomprasert; Piyada Jittangprasert; Prapin Wilairat; Praveena Yamanont; Udom Chantharaksri; Suthat Fucharoen; Noppawan Phumala Morales
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical pharmacokinetics     Volume:  50     ISSN:  0312-5963     ISO Abbreviation:  Clin Pharmacokinet     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-14     Completed Date:  2011-03-18     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  7606849     Medline TA:  Clin Pharmacokinet     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  41-50     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Adult
Area Under Curve
Blood Transfusion / adverse effects
Female
Ferritins / metabolism
Hemoglobin E / analysis
Humans
Iron / pharmacokinetics*
Iron Chelating Agents / administration & dosage,  pharmacokinetics*,  therapeutic use
Iron Overload / blood,  drug therapy,  etiology
Male
Pyridones / administration & dosage,  pharmacokinetics*,  therapeutic use
Splenectomy
Transferrin / metabolism
beta-Thalassemia / blood*,  therapy
Chemical
Reg. No./Substance:
0/Iron Chelating Agents; 0/Pyridones; 0/Transferrin; 2BTY8KH53L/deferiprone; 7439-89-6/Iron; 9007-73-2/Ferritins; 9034-61-1/Hemoglobin E

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