Search

14C-labeled YH4808, a novel potassium-competitive acid blocker, was intravenously administered as a microtracer at 80 μg (11.8 kBq or 320 nCi) concomitantly with the nonradiolabeled oral drug at 200 mg to determine the absolute bioavailability and to assess the effect of pharmacogenomics on the oral absorption of YH4808. The absolute bioavailability was low and highly variable (mean, 10.1%; range, 2.3-19.3%), and M3 and M8, active metabolites of YH4808, were formed 22.6- and 38.5-fold higher after oral administration than intravenous administration, respectively. The product of the fraction of an oral YH4808 dose entering the gut wall and the fraction of YH4808 passing on to the portal circulation was larger in subjects carrying the variants of the CHST3, SLC15A1, and SULT1B1 genes. A combined LC+AMS is a useful tool to construct a rich and highly informative pharmacokinetic knowledge core in early clinical drug development at a reasonable cost. [ABSTRACT FROM AUTHOR]

Decreased oral clopidogrel absorption caused by induction of intestinal permeability glycoprotein (P-gp) expression after aspirin administration was observed in rats. This study evaluated the effect of aspirin coadministration on the pharmacokinetics/pharmacodynamics of clopidogrel in humans. A single 75-mg dose of clopidogrel was orally administered before and after 2 and 4 weeks of once-daily 100-mg aspirin administration in 18 healthy volunteers who were recruited based on CYP2C19 and PON1 genotypes. Plasma concentrations of clopidogrel and its active metabolite, H4, and relative platelet inhibition (RPI) were determined. The P-gp microRNA miR-27a increased by up to 7.67-fold (P = 0.004) and the clopidogrel area under the concentration-time curve (AUC) decreased by 14% (P > 0.05), but the AUC of H4 remained unchanged and RPI increased by up to 15% (P = 0.002) after aspirin administration. These findings indicate low-dose aspirin coadministration may decrease clopidogrel bioavailability but does not decrease its efficacy. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate endogenous metabolic markers of hepatic cytochrome P450 (CYP)3A activity in healthy subjects using a metabolomics approach. Twenty-four subjects received the following medication during the following three study periods: 1 mg of i.v. midazolam alone (control phase), 1 mg of i.v. midazolam after 4 days of pretreatment with 400 mg of ketoconazole once daily (CYP3A-inhibited phase), and 2.5 mg of i.v. midazolam after 10 days of pretreatment with 600 mg of rifampicin once daily (CYP3A-induced phase). During each study period, 24 h before and after the administration of midazolam, urine samples were collected at 12-h intervals for metabolomic analyses. We derived an equation to predict midazolam clearance (CL) based on several of these markers. We demonstrated that a combination of the concentrations and ratios of several endogenous metabolites and the CYP3A5*3 genotype is a reliable predictive marker of hepatic CYP3A activity as assessed by i.v. administration of midazolam. [ABSTRACT FROM AUTHOR]

Objective To establish human renal cell carcinoma (RCC) cell lines, and to investigate the cell phenotypes and molecular characteristics of human RCC cell lines and their corresponding tumour tissues. Materials and methods Seven human RCC cell lines from pathologically proven RCCs were established. The histopathology of the primary tumours, in vitro growth characteristics and status of tumour suppressor genes, mismatch repair genes and microsatellite instability (MSI) were examined in cell lines and their corresponding tumour tissues. Five of the cell lines were derived from clear cells (SNU‐228, ‐267, ‐328, ‐349, and ‐1272), one from granular cells (SNU‐482), and one from mixed clear and granular cell types (SNU‐333). The mutational status was compared for von Hippel‐Lindau (VHL), p53, TGF‐β type II receptor (TGF‐βRII), hMSH2, and hMLH1 genes in the cell lines and their corresponding tumour tissues. The MSI status of the cell lines was determined by screening for adenine repeat sequences, e.g. BAT‐25, BAT‐26, and BAT‐40. Results All lines showed different doubling times and were confirmed by DNA fingerprinting analysis to be unique. Contamination by mycoplasma or bacteria was excluded. In two cell lines (SNU‐349 and ‐1272) and their tumour tissues, mutations in the VHL gene were found. The SNU‐267 line had a frameshift mutation in the p53 gene. A missense mutation of the TGF‐βRII gene was detected in the SNU‐1272 line and the corresponding tissue. Analysis of the repeat sequences showed one cell line (SNU‐349) to have MSI and the other six to have microsatellite stability. As MSI is a hallmark of the inactivation of mismatch repair genes, the presence of hMSH2 and hMLH1 mutations was investigated in all seven cell lines. An inactivating homozygous single base‐pair deletion of the hMLH1 gene was found only in the SNU‐349 cell line and corresponding tissue. Moreover, a frameshift mutation within an 8‐bp polyadenine repeat present in the hMSH3 coding region was found only in the MSI cell line and tumour tissue. Conclusion These newly established RCC cell lines should provide a useful in vitro model for studies related to human RCC. The SNU‐349 cell line should be especially useful for studies of MSI and mismatch repair‐defective RCCs. [ABSTRACT FROM AUTHOR]

The new allele B*40:186 shows a one nucleotide substitution compared with B*40:01:02 at codon 56 ( GGG → AGG) resulting in coding change, Gly to Arg. [ABSTRACT FROM AUTHOR]