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Background and objectives:  Cholelithiasis has been observed with high incidence in beta-thalassemia/hemoglobin E (β-thal/Hb E). Recent studies have shown that a variant TATA-box in the promoter region of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene is associated with the development of cholelithiasis. The coding region mutation (G71R) of the UGT1A1 gene was higher in Asians than those in Caucasians. The relationship between the variant UGT1A1 promoter and coding region gene and cholelithiasis in β-thal/Hb E subjects were investigated. Methods:  One hundred and seventeen β-thal/Hb E subjects entered this study. The TATA-box and G71R mutations were analyzed by fragment size analysis and restriction fragment length polymorphism methods, respectively. Results:  The incidence of cholelithiasis was higher in heterozygous (68.3%) and homozygous (100%) subjects compared with normal UGT1A1 haplotype (61.4%). Total bilirubin level (6.0 ± 2.03 mg/dL) in the homozygous group was significantly higher than that of wild type (3.31 ± 1.83 ng/dL). Prevalence of cholelithiasis increased with age (OR = 1.1, 95% CI = 1.03–1.12, P < 0.001). Female gender (OR = 3.7, 95% CI = 1.3–10.6, P < 0.01) and elevated liver enzyme (OR = 1.02, 95%CI = 1.0–1.04, P < 0.02) were two other risk factors for cholethiasis in β-thal/Hb E. Conclusion:  This study shows that the combined TATA-box variants and G71R mutations of the UGT1A1 is associated with cholelithiasis in β-thal/Hb E. [ABSTRACT FROM AUTHOR]

In addition to pathophysiological changes, genetic variations can alter drug pharmacokinetics in patients with thalassemia. Numerous drugs are metabolized by UDP-glucuronosyltransferases (UGT) including paracetamol (PCM), a widely used analgesic. Co-occurrence of the UGT1A1 polymorphism (UGT1A1*28) and the UGT1A6 polymorphism (UGT1A6*2) may affect PCM glucuronidation. To elucidate the effect of these combined polymorphisms on the PCM metabolism in thalassemic patients, 15 β-thalassemia/hemoglobin E subjects with three different UGT1A genotypes received a single oral dose of 1,000 mg PCM. Drug disposition was determined by HPLC. Patients who have UGT1A6*2 without UGT1A1*28 showed a significant, lower area under concentration-time curve (AUC0→∞) of PCM, PCM-glucuronide and PCM-sulfate than those of the patients with wild-type UGT1A1 and UGT1A6 (p < 0.05). In addition, a high elimination rate constant and clearance of PCM and its metabolites were also found in these patients (p < 0.05). Ourstudy suggests that a subtherapeutic level of PCM may occur in patients who have UGT1A6*2 without UGT1A1*28. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Thalassemia may alter the pharmacokinetics of several drugs in thalassemic patients. Paracetamol is a commonly used analgesic and antipyretic drug which is extensively metabolized in the liver via glucuronidation. The aim of this study was to compare the pharmacokinetics of paracetamol (PCM) and its metabolites [paracetamol glucuronide (PCM-G), paracetamol sulfate (PCM-S), and paracetamol cysteine (PCM-C)] in 16 patients with 16 normal subjects. Following an overnight fast, a single dose of paracetamol (1,000 mg of Tylenol®) was given and blood samples were obtained at predose, 0.5, 1, 1.5, 2, 3, 4, 5, 7, and 9 h after dosing for determination of the plasma levels of PCM and its metabolites by high-performance liquid chromatography. There was no significant difference in maximum concentration of PCM between groups. However, a significantly shorter elimination half-life of PCM was observed in the thalassemic subjects ( p<0.001). Total apparent clearance of PCM was significantly faster in thalassemic subjects ( p<0.01) while the apparent volume of distribution of PCM did not change. The area under the concentration time curve (AUC0->∞) of PCM-G and PCM-S increased in thalassemic subjects ( p<0.05) whereas this parameter for PCM-C was slightly lower in the patients. The half-lives of PCM metabolites were significantly shorter ( p<0.01) in thalassemic subjects. The results indicate that the elimination of PCM and its metabolites in thalassemic subjects is faster than that in normal subjects. Our pharmacokinetic data provide additional evidence that plasma PCM-G is higher in thalassemic patients with hyperbilirubinemia, which could be a casual relationship in regulating the UDP-glucuronosyltransferase expression. [ABSTRACT FROM AUTHOR]

Dose-related pharmacokinetics and urinary iron excretion (UIE) of an orally active iron chelator, deferiprone (L1), was investigated in 12 severe β-thalassemia/hemoglobin E patients. The patients received two single doses of 25 and 50 mg/kg with a 2-week washout period. Deferiprone was rapidly absorbed and reached maximum concentration (Cmax) within 1 h after administration. Pharmacokinetic parameters including Cmax and area under concentration time curve from time zero to infinity (AUC0-∞) as well as urinary excretion of non-conjugated and glucuronide-conjugated deferiprone (L1 and L1-G) increased proportionally with the dose of deferiprone. A constant ratio of AUC0-∞ of L1-G to L1 and a percentage of urinary excretion of L1-G indicated that increasing the dosage does not influence deferiprone biotransformation. Longer terminal elimination half-lifeand higher volume of distribution of L1 were observed with the high dose and correlated with deferiprone-chelated iron in serum. Unexpectedly, UIE did not show a linear relationship with the increased dose of deferiprone. The correlation between UIE and creatinine clearance suggested the possibility of L1-iron complex redistribution in patients with renal impairment treated with high-dose deferiprone. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The method for the determination of primaquine (PQ) and 5,6-orthoquinone primaquine (5,6-PQ), the representative marker for PQ active metabolites, via CYP2D6 in human plasma and urine has been validated. All samples were extracted using acetonitrile for protein precipitation and analyzed using the ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) system. Chromatography separation was carried out using a Hypersil GOLDTM aQ C18 column (100 × 2.1 mm, particle size 1.9 μm) with a C18 guard column (4 × 3 mm) flowed with an isocratic mode of methanol, water, and acetonitrile in an optimal ratio at 0.4 mL/min. The retention times of 5,6-PQ and PQ in plasma and urine were 0.8 and 1.6 min, respectively. The method was validated according to the guideline. The linearity of the analytes was in the range of 25–1500 ng/mL. The matrix effect of PQ and 5,6-PQ ranged from 100% to 116% and from 87% to 104% for plasma, and from 87% to 89% and from 86% to 87% for urine, respectively. The recovery of PQ and 5,6-PQ ranged from 78% to 95% and form 80% to 98% for plasma, and from 102% to from 112% to 97% to 109% for urine, respectively. The accuracy and precision of PQ and 5,6-PQ in plasma and urine were within the acceptance criteria. The samples should be kept in the freezer (−80 °C) and analyzed within 7 days due to the metabolite stability. This validated UHPLC-MS/MS method was beneficial for a pharmacokinetic study in subjects receiving PQ. [ABSTRACT FROM AUTHOR]