Limenta Lie Michael George, Jirasomprasert Totsapol, Tankanitlert Jeeranut, Svasti Saovaros, Wilairat Prapin, Chantharaksri Udom, Fucharoen Suthat, Morales Noppawan Phumala
Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Br J Clin Pharmacol. 2008 Jun;65(6):908-16. doi: 10.1111/j.1365-2125.2008.03103.x. Epub 2008 Mar 3.
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.
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.
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.
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 AUC(0-infinity), V(d)/F, and CL/F of deferiprone. Gender differences in 24-h urinary deferiprone and its metabolite excretion, however, failed to reach statistical significance. The V(d)/F of deferiprone was found to correlate significantly with serum ferritin (r(s) = 0.665; P = 0.001).
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.
UGT1A6被认为是负责去铁酮葡萄糖醛酸化的主要同工酶。UGT1A6*2等位基因与酶活性改变有关。
UGT1A6基因型对健康志愿者单次给药去铁酮的药代动力学无统计学显著影响。性别影响去铁酮的血清药代动力学。血清铁蛋白水平反映的机体铁储备可能对去铁酮血管外分布程度有影响。目的是研究UGT1A6基因多态性对健康志愿者去铁酮药代动力学的影响。
招募22名健康志愿者并根据UGT1A6基因型分组。过夜禁食后，受试者单次口服25 mg·kg-1去铁酮。给药后0、15、30、45、60、90、120、180、240、300和360分钟采集血样。0、0 - 2、2 - 4、4 - 8、8 - 12和12 - 24小时收集尿量。采用经过验证的高效液相色谱法测定血清和尿液中去铁酮（L1）和去铁酮葡萄糖醛酸苷（L1G）的浓度。通过聚合酶链反应 - 限制性片段长度多态性分析确定UGT1A6基因型。
各基因型组去铁酮或去铁酮葡萄糖醛酸苷的任何药代动力学参数均无统计学显著差异。同样，各基因型组24小时尿去铁酮和去铁酮葡萄糖醛酸苷排泄也无统计学显著差异。在去铁酮的AUC(0-∞)、V(d)/F和CL/F方面，男性和女性存在显著差异。然而，24小时尿去铁酮及其代谢产物排泄的性别差异未达到统计学显著性。发现去铁酮的V(d)/F与血清铁蛋白显著相关（r(s)=0.665；P = 0.001）。
UGT1A6中研究的单核苷酸多态性似乎对去铁酮单次给药的药代动力学无统计学显著影响。性别似乎影响去铁酮的血清药代动力学，但不影响去铁酮及其代谢产物的尿排泄。机体铁储备可能对去铁酮血管外分布程度有影响。
