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 C(max) and AUC) of deferiprone glucuronide and deferiprone-chelated iron, as well as a significant increase in UIE.

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.

Gender and body weight were covariates that contributed most to explaining the observed interindividual alcohol pharmacokinetic variability. Of the four SNPs examined in this study, only ADH1B Arg48His polymorphism had a significant, though modest, effect on the pharmacokinetics of alcohol.

Background and Objective As of December 2017, 20 diabetic ketosis (DK)/diabetic ketoacidosis (DKA) cases associated with sodium–glucose co-transporter 2 inhibitors (SGLT2i) had been reported to the Health Sciences Authority (HSA), Singapore. We aimed to provide a detailed analysis of the profile of these cases. Methods As part of the emerging safety issue monitoring, the HSA followed up on SGLT2i-associated DK/DKA cases with the reporters to obtain the missing and/or supplementary information. Descriptive statistics were employed to summarise the data collected, while the Mann–Whitney test was employed to evaluate the differences between typical and euglycaemic DKA cases as well as between genders. Results All cases led to hospitalisation but were non-fatal. Where reported, the majority (71–85%) of DK/DKA cases occurred within 180 days of SGLT2i therapy initiation and involved female patients and/or patients with long-standing type 2 diabetes mellitus (T2DM). Apart from the difference in blood glucose levels, no differences in the profile between the typical and euglycaemic DKA cases were noted. Known precipitating factors were identified in all cases. Acute illnesses, particularly infections and abscesses, were the most commonly reported precipitating factors, followed by insulin dose reduction/cessation. Conclusions Based on the profile of the reported cases, it is imperative to maintain clinical vigilance for DK/DKA, especially during the first 6 months of SGLT2i treatment and more so in female patients and/or patients with long-standing T2DM. Prompt evaluation and management of underlying precipitating factors is also important to assess and mitigate the risk of developing DK/DKA during treatment with SGLT2i.

The novel organic cation transporter 1 (OCTN1) is a multispecific, bidirectional and pH-dependent organic cation transporter with low carnitine transport activity. It is a transporter of the physiological substance ergothioneine and mediates the transport of a variety of organic cations such as tetraethylammonium, pyrilamine and quinidine. This study identifies genetic variations of the SLC22A4 gene in two distinct ethnic groups of the Singaporean population (n=192) by DNA sequencing. Twenty four genetic variants of SLC22A4, including 14 found to be novel. 16 in the coding exons (10 nonsynonymous and 6 synonymous variations) and 8 in the introns. Among the novel nonsynonymous variations, Arg63His, Arg83Pro, Met344Lys and Ile500Asn were predicted to be functionally significant. These data should provide fundamental and useful information for pharmacogenetic studies on drugs that are substrates of OCTN1 in Asians.