title: Pharmacokinetics of Deferiprone in Patients with β-Thalassaemia : Impact of Splenectomy and Iron Status.
abstract: 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 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 β-thalassaemia/haemoglobin E, and the present study was aimed at examining this hypothesis.
  
  
  METHODS
  Thirty-one patients with β-thalassaemia/haemoglobin E (20 splenecto-mized 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 body weight. 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 (Cmax) 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 53.2µmol/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 Cmaxand the AUC from 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 mmol · min/L and 77.1 mmol, respectively) than in non-splenectomized patients (median values 3.1 µmol/L, 545 mmol · 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 AUClastof deferiprone-chelated iron and UIE.
  
  
  CONCLUSIONS
  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 Cmaxand AUC) of deferiprone glucuronide and deferiprone-chelated iron, as well as a significant increase in UIE.
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Rama 6 Rd, Rajatevee, Bangkok, 10400, Thailand.
authors.forename: Lie Michael George
authors.initials: LM
authors.lastname: Limenta
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Rama 6 Rd, Rajatevee, Bangkok, 10400, Thailand.
authors.forename: Totsapol
authors.initials: T
authors.lastname: Jirasomprasert
authors.affiliation: Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand.
authors.forename: Piyada
authors.initials: P
authors.lastname: Jittangprasert
authors.affiliation: Department of Chemistry, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Prapin
authors.initials: P
authors.lastname: Wilairat
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Rama 6 Rd, Rajatevee, Bangkok, 10400, Thailand.
authors.forename: Praveena
authors.initials: P
authors.lastname: Yamanont
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Rama 6 Rd, Rajatevee, Bangkok, 10400, Thailand.
authors.forename: Udom
authors.initials: U
authors.lastname: Chantharaksri
authors.affiliation: Thalassemia Research Center, Institute of Molecular Bioscience, Mahidol University, Salaya Campus, Nakornpathom, Thailand.
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Rama 6 Rd, Rajatevee, Bangkok, 10400, Thailand. scnpm@mahidol.ac.th.
authors.forename: Noppawan Phumala
authors.initials: NP
authors.lastname: Morales