| Pharmacokinetics of deferiprone in patients with β-thalassaemia: impact of splenectomy and iron status. | |
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MedLine Citation:
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PMID: 21028920 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Lie Michael George Limenta; Totsapol Jirasomprasert; Piyada Jittangprasert; Prapin Wilairat; Praveena Yamanont; Udom Chantharaksri; Suthat Fucharoen; Noppawan Phumala Morales |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Clinical pharmacokinetics Volume: 50 ISSN: 0312-5963 ISO Abbreviation: Clin Pharmacokinet Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-14 Completed Date: 2011-03-18 Revised Date: 2012-02-29 |
Medline Journal Info:
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Nlm Unique ID: 7606849 Medline TA: Clin Pharmacokinet Country: New Zealand |
Other Details:
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Languages: eng Pagination: 41-50 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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0/Iron Chelating Agents; 0/Pyridones; 0/Transferrin; 30652-11-0/deferiprone; 7439-89-6/Iron; 9007-73-2/Ferritins; 9034-61-1/Hemoglobin E |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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