The Comparative Metabolism of a Novel Hepatocellular Carcinoma Therapeutic Agent, 2,3-Diamino-N-(4-(benzo[d]thiazol-2-yl)phenyl)propanamide, in Human and Animal Hepatocytes.

[2,3-diamino-N-(4-(benzo[d]thiazol-2-yl)phenyl)propanamide], named as ETN101, is a novel therapeutic agent for hepatocellular carcinoma. In vitro studies examined ETN101 metabolites in human, mouse, rat, dog, and monkey hepatocytes and identified the drug-metabolizing enzymes involved using cDNA-expressed human recombinant cytochrome P450s (CYPs), carboxylesterases (CESs), N-acetyltransferase (NAT) 1, and human liver cytosol. ETN101 showed similar metabolic stability across hepatocytes from five species, with particularly comparable stability in humans, rats, and monkeys. Its half-life was 75.0 min in humans, 68.9 in rats, 73.1 in monkeys, 120.4 in mice, and 112.7 in dogs. Thirty-four ETN101 metabolites, including the major metabolite M1, were identified using liquid chromatography-high-resolution mass spectrometry. ETN101 was primarily metabolized to M1 and CYP1A2 is exclusively responsible for M1 metabolism. Both NAT1 and NAT2 were responsible for the N-acetylation of M1 to M2. ETN101 remained stable in human CESs. In conclusion, this study provides comprehensive insights into the metabolic characteristics of ETN101, valuable for its toxicological and clinical development.

Effect of concomitant oral administration of ethanol on the pharmacokinetics of nicardipine in rats.

Ethanol intake can alter pharmacokinetics by increasing the solubility or enhancing the absorption of concomitant drugs. Here, a selective, sensitive and reproducible high-performance liquid chromatography-tandem mass spectrometry method for the quantitative analysis of nicardipine in rat plasma was developed using simple protein precipitation. The calibration curve was linear over a concentration range of 1-2,000 ng/ml (r2 > 0.998). Accuracy ranged from 93.4 to 112.2% and precision was within 12.1% from three independent analytical batches. Stable conditions for the quantification of nicardipine in rat plasma were established in various conditions, including sample storage and handling. The matrix effect was negligible, and recovery was consistent at three different levels of quality control sample. The method was applied to assessment for the effect of ethanol on the pharmacokinetics of nicardipine in rats. The oral bioavailability of nicardipine was increased from 5.4 to 9.4% in Sprague-Dawley rats by concomitant oral administration of ethanol whereas the half-life was not altered. The findings indicated that concomitant ethanol intake can increase systemic drug exposure by increasing gastrointestinal absorption, especially poorly soluble drugs. This study provides an insight for further investigation of the alteration of the pharmacological effect of poorly soluble drugs owing to ethanol intake.

Simultaneous determination of perfluorooctanoic acid and perfluorooctanesulfonic acid in Korean sera using LC-MS/MS.

Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are synthetic chemicals that have been used in various industries and household products. These can easily accumulate in the human body, causing adverse effects on human health. In this study, a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous analysis of PFOA and linear PFOS in human serum. Owing to a lack of PFOA- and PFOS-free human serum, 13C8-PFOA and 13C8-PFOS were used as surrogate analytes for quantification. A sensitive and selective sample preparation method was developed and optimized by combining solid-phase extraction and protein precipitation method. The lower limit of quantification was 0.05 ng/mL, and the analytical response was linear up to 10 ng/mL for both PFOA and linear PFOS. Chromatographic separation of the linear PFOS from branched isomers was achieved within 5.5 min. The method was validated at various concentrations and afforded acceptable accuracy and precision values. After validation, the method was successfully applied to evaluate the exposure levels of PFOA and linear PFOS in the Korean population. The serum concentrations of PFOA and linear PFOS were 0.42-28.3 ng/mL and 0.81-57.6 ng/mL, respectively. The median concentration of linear PFOS was approximately 2.6-fold higher than that of PFOA. The concentration of PFOA was higher in women than men (p < 0.05) and that of linear PFOS was not significantly different between men and women. Therefore, a sensitive, selective, and reliable bioanalytical method was developed and validated. This method can potentially be applied to biomonitoring studies involving PFOA and linear PFOS.