Endogenous metabolic markers for predicting the activity of dihydropyrimidine dehydrogenase

Five-fluorouracil (5-FU) is a chemotherapeutic agent that is mainly metabolized by the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). The DPD enzyme activity deficiency involves a wide range of severities. Previous studies have demonstrated the effect of a DPYD single nucleotide polymorphism on 5-FU efficacy and highlighted the importance of studying such genes for cancer treatment. Common polymorphisms of DPYD in European ancestry populations are less frequently present in Koreans. DPD is also responsible for the conversion of endogenous uracil (U) into dihydrouracil (DHU). We quantified U and DHU in plasma samples of healthy male Korean subjects, and samples were classified into two groups based on DHU/U ratio. The calculated DHU/U ratios ranged from 0.52 to 7.12, and the two groups were classified into the 10th percentile and 90th percentile for untargeted metabolomics analysis using liquid chromatography-quantitative time-of-flight-mass spectrometry. A total of 4440 compounds were detected and filtered out based on a coefficient of variation below 30%. Our results revealed that six metabolites differed significantly between the high activity group and low activity group (false discovery rate q-value \u3c 0.05). Uridine was significantly higher in the low DPD activity group and is a precursor of U involved in pyrimidine metabolism; therefore, we speculated that DPD deficiency can influence uridine levels in plasma. Furthermore, the cutoff values for detecting DPD deficient patients from previous studies were unsuitable for Koreans. Our metabolomics approach is the first study that reported the DHU/U ratio distribution in healthy Korean subjects and identified a new biomarker of DPD deficiency

Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials

Conventional reversal of rocuronium-induced neuromuscular blockade by sugammadex in Korean children: pharmacokinetics, efficacy, and safety analyses

Background: Sugammadex is known to reverse neuromuscular blockade induced by non-depolarizing agents. In children, the recommended dose for reversal of moderate neuromuscular blockade is 2 mg/kg. We investigated the pharmacokinetics and pharmacodynamics of sugammadex in Korean children.Methods: Children (2–17 years of age) undergoing brain or spine surgery were enrolled and randomly assigned to control (neostigmine) and 2, 4, or 8 mg/kg sugammadex groups. Following induction of anesthesia and monitoring of the response to train-of-four stimulation, 1 mg/kg rocuronium was intravenously administered. Upon reappearance of the second twitch to train-of-four stimulation, the study drug was administered according to group allocation. The plasma concentrations of rocuronium and sugammadex were serially measured at nine predefined time points following study drug administration. To determine efficacy, we measured the time elapsed from drug administration to recovery of T4/T1 ≥ 0.9. For pharmacokinetics, non-compartmental analysis was performed and we monitored adverse event occurrence from the time of study drug administration until 24 h post-surgery.Results: Among the 29 enrolled participants, the sugammadex (2 mg/kg) and control groups showed recovery times [median (interquartile range)] of 1.3 (1.0–1.9) and 7.7 (5.3–21.0) min, respectively (p = 0.002). There were no significant differences in recovery time among the participants in sugammadex groups. The pharmacokinetics of sugammadex were comparable to those of literature findings. Although two hypotensive events related to sugammadex were observed, no intervention was necessary.Conclusion: The findings of this pharmacokinetic analysis and efficacy study of sugammadex in Korean children indicated that sugammadex (2 mg/kg) may be safely administered for reversing moderate neuromuscular blockade. Some differences in pharmacokinetics of sugammadex were observed according to age.Clinical Trial Registration:http://clinicaltrials.gov (NCT04347486

A database of 5305 healthy Korean individuals reveals genetic and clinical implications for an East Asian population

Despite substantial advances in disease genetics, studies to date have largely focused on individuals of European descent. This limits further discoveries of novel functional genetic variants in other ethnic groups. To alleviate the paucity of East Asian population genome resources, we established the Korean Variant Archive 2 (KOVA 2), which is composed of 1896 whole-genome sequences and 3409 whole-exome sequences from healthy individuals of Korean ethnicity. This is the largest genome database from the ethnic Korean population to date, surpassing the 1909 Korean individuals deposited in gnomAD. The variants in KOVA 2 displayed all the known genetic features of those from previous genome databases, and we compiled data from Korean-specific runs of homozygosity, positively selected intervals, and structural variants. In doing so, we found loci, such as the loci of ADH1A/1B and UHRF1BP1, that are strongly selected in the Korean population relative to other East Asian populations. Our analysis of allele ages revealed a correlation between variant functionality and evolutionary age. The data can be browsed and downloaded from a public website (https://www.kobic.re.kr/kova/). We anticipate that KOVA 2 will serve as a valuable resource for genetic studies involving East Asian populations

A combinatorial model for the transition matrix between the Specht and SL⁡2\operatorname {SL}_2 -web bases

We introduce a new class of permutations, called web permutations. Using these permutations, we provide a combinatorial interpretation for entries of the transition matrix between the Specht and $\operatorname {SL}_2$ -web bases of the irreducible $\mathfrak {S}_{2n}$ -representation indexed by $(n,n)$ , which answers Rhoades’s question. Furthermore, we study enumerative properties of these permutations

Stretching symmetry and Haglund's conjecture for Macdonald polynomials

We provide new approaches to prove identities for the modified Macdonald polynomials: using the LLT expansion of the modified Macdonald polynomials and using the Garsia--Haiman module. We prove a stretching symmetry for the modified Macdonald polynomials of one-column shape. We also prove a conjecture of Haglund concerning multi-$t$-Macdonald polynomials of two rows.Comment: After posting the old version on arxiv, we learned that Conjecture 1.1 in the old version follows from a result of Garsia-Tesler. We changed it to Theorem and add some comment