UGT1A6 genotype‐related pharmacokinetics of deferiprone (L1) in healthy volunteers

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • UGT1A6 has been proposed as the predominant isoform responsible for the glucuronidation of deferiprone. • UGT1A6*2 allele has been associated with the altered enzyme activity. WHAT THIS STUDY ADDS • There is no statistically significant effect of UGT1A6 genotype on the single‐dose pharmacokinetics of deferiprone in healthy volunteers. • Gender influences serum pharmacokinetics of deferiprone. • Body iron stores reflected by serum ferritin levels may have an influence on the extent of extravascular deferiprone distribution. AIMS To examine the effects of UGT1A6 polymorphisms on the pharmacokinetics of deferiprone in healthy volunteers. METHODS Twenty‐two healthy volunteers were enrolled and grouped according to UGT1A6 genotype. After an overnight fast, the subjects received a single oral dose of 25 mg kg−1 deferiprone. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min after dosing. Urine output was collected at 0, 0–2, 2–4, 4–8, 8–12 and 12–24 h. Deferiprone (L1) and deferiprone‐glucuronide (L1G) concentrations in serum and urine were determined using a validated high‐performance liquid chromatography method. UGT1A6 genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism analysis. RESULTS No statistically significant differences in any pharmacokinetic parameters of either deferiprone or deferiprone‐glucuronide among the genotype groups were noted. Likewise, there were no statistically significant differences in 24‐h urinary deferiprone and deferiprone‐glucuronide excretion among the genotype groups. Significant differences between men and women were found in AUC0–∞, Vd/F, and CL/F of deferiprone. Gender differences in 24‐h urinary deferiprone and its metabolite excretion, however, failed to reach statistical significance. The Vd/F of deferiprone was found to correlate significantly with serum ferritin (rs = 0.665; P = 0.001). CONCLUSION The studied single nucleotide polymorphisms in UGT1A6 do not appear to exert statistically significant effects on the single‐dose pharmacokinetics of deferiprone. Gender appears to influence the serum pharmacokinetics of deferiprone, but not urinary excretion of deferiprone and its metabolite. Body iron stores may have an influence on the extent of extravascular deferiprone distribution.

Inhibitory Effects of Commonly Used Herbal Extracts on UDP-Glucuronosyltransferase 1A4, 1A6, and 1A9 Enzyme Activities

“…UGT1A6 is typically a low-affinity enzyme that catalyzes glucuronidation of drug substrates including acetaminophen, naproxen, and deferiprone (Bowalgaha et al, 2005;Kiang et al, 2005;Limenta et al, 2008). Milk thistle and saw palmetto inhibited serotonin glucuronidation with IC 50 concentrations attainable if the daily doses of milk thistle (600 mg) or saw palmetto (320 mg) are diluted with 6.3 and 3.1 liters, respectively.…”

Deferiprone (GPO‐L‐ONE®) monotherapy reduces iron overload in transfusion‐dependent thalassemias: 1‐year results from a multicenter prospective, single arm, open label, dose escalating phase III pediatric study (GPO‐L‐ONE; A001) from Thailand

“…The program has started in 2001 from synthesizing compound from raw material, testing the product for all international chemical and biochemical standard, evaluating bioequivalence with original product to finally determining pharmacokinetic profiles in healthy volunteers and thalassemia patients [23][24][25].…”

Comparison of Pharmacokinetics and Urinary Iron Excretion of Two Single Doses of Deferiprone in ß-Thalassemia/Hemoglobin E Patients

“…Our previous study demonstrated that the pathophysiology of patients, including iron status and splenectomy, influenced pharmacokinetics and UIE [13]. Genetic polymorphism of the drug-metabolizing enzyme (UGT1A6) did not play a significant role in the variation [14].…”

“…Glucuronide Methods of analysis were described in our previous report [13,14]. Briefly, serum samples were deproteinized by ultrafiltration with Amicon Centrifree® micropartition devices (Millipore Corp., Bedford, Mass., USA).…”