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dc.contributor.authorLimenta L.M.G.
dc.contributor.authorJirasomprasert T.
dc.contributor.authorJittangprasert P.
dc.contributor.authorWilairat P.
dc.contributor.authorYamanont P.
dc.contributor.authorChantharaksri U.
dc.contributor.authorFucharoen S.
dc.contributor.authorMorales N.P.
dc.description.abstractBackground and Objective: Iron-rich transfusions and/or a compensatory increase in iron absorption ultimately result in iron loading in patients with b-thalassaemia. Hence, without iron chelation, iron accumulates relentlessly. Deferiprone has been shown to be capable of reducing the iron burden in patients with b-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 b-thalassaemia/haemoglobin E, and the present study was aimed at examining this hypothesis. Study Participants and Methods: Thirty-one patients with b-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 25mg/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 1 ) 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 mmol • min/L, respectively). The Cmax and the AUCfrom time zero to the time of the last measurable concentration (AUClast) 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 AUClast 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 (theCmax and AUC) of deferiprone glucuronide and deferipronechelated iron, as well as a significant increase in UIE. © 2011 Adis Data Information BV. All rights reserved.
dc.subjectdeferiprone glucuronide
dc.subjectdrug metabolite
dc.subjectgpo l1
dc.subjecthemoglobin E
dc.subjectiron chelate
dc.subjectunclassified drug
dc.subjectarea under the curve
dc.subjectbeta thalassemia
dc.subjectblood sampling
dc.subjectdiet restriction
dc.subjectdrug activity
dc.subjectdrug blood level
dc.subjectdrug conjugation
dc.subjectdrug efficacy
dc.subjectdrug urine level
dc.subjecthigh performance liquid chromatography
dc.subjectiron binding capacity
dc.subjectiron blood level
dc.subjectiron chelation
dc.subjectiron metabolism
dc.subjectiron overload
dc.subjectmaximum plasma concentration
dc.subjectmultiple linear regression analysis
dc.subjectplasma concentration-time curve
dc.subjectpriority journal
dc.subjectsingle drug dose
dc.subjecturinary excretion
dc.subjecturine volume
dc.subjectAdministration, Oral
dc.subjectArea Under Curve
dc.subjectBlood Transfusion
dc.subjectHemoglobin E
dc.subjectIron Chelating Agents
dc.subjectIron Overload
dc.titlePharmacokinetics of deferiprone in patients with β-thalassaemia: Impact of splenectomy and iron status
dc.identifier.bibliograpycitationClinical Pharmacokinetics. Vol 50, No.1 (2011), p.41-50
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