Amid revolutionary changes in toxicity assessment brought about by increasing regulation of chemicals, adverse outcome pathways (AOPs) have emerged as a useful framework to assess adverse effect of chemicals using molecular level effect, which aid in setting environmental regulation policies. AOPs are biological maps that describe mechanisms linking molecular initiating event to adverse outcomes (AOs) at an individual level. Each AOP consists of a molecular initiating event, key events, and an AO. AOPs use molecular markers to predict endpoints currently used in risk assessment, promote alternatives to animal model-based test methods, and provide scientific explanations for the effects of chemical exposures. Moreover, AOPs enhance certainty in interpreting existing and new information. The application of AOPs in chemical toxicity testing will help shift the existing paradigm of chemical management based on apical endpoints toward active application of in silico and in vitro data.
Animals ; Computer Simulation ; In Vitro Techniques ; Risk Assessment ; Toxicity Tests*

Amid revolutionary changes in toxicity assessment brought about by increasing regulation of chemicals, adverse outcome pathways (AOPs) have emerged as a useful framework to assess adverse effect of chemicals using molecular level effect, which aid in setting environmental regulation policies. AOPs are biological maps that describe mechanisms linking molecular initiating event to adverse outcomes (AOs) at an individual level. Each AOP consists of a molecular initiating event, key events, and an AO. AOPs use molecular markers to predict endpoints currently used in risk assessment, promote alternatives to animal model-based test methods, and provide scientific explanations for the effects of chemical exposures. Moreover, AOPs enhance certainty in interpreting existing and new information. The application of AOPs in chemical toxicity testing will help shift the existing paradigm of chemical management based on apical endpoints toward active application of in silico and in vitro data.
Animals ; Computer Simulation ; In Vitro Techniques ; Risk Assessment ; Toxicity Tests

Fetal tachycardia (FT) is a rare disorder and is associated with significant mortality of fetus. Digoxin is one of the antiarrhythmic agents used to treat FT via transplacental therapy. In this report, we describe a therapeutic drug monitoring (TDM) case of digoxin during the treatment of FT. A 40-year-old woman, gravida 2 para 1, hospitalized to control FT as the fetal heart rate (FHR) showed over 200 bpm on ultrasonography at 29 weeks of gestation. She did not have any medical or medication history and showed normal electrolytes level on clinical laboratory test results. For the treatment of FT loading and maintenance dose of intravenous digoxin (loading dose: 0.6 mg; maintenance dose: 0.3 mg every 8 hours) were administered. To monitor the efficacy and safety of the treatment, TDM was conducted with a target maternal serum trough digoxin concentration of 1.0 to 2.0 ng/mL, as well as ultrasonography and maternal electrocardiogram. The observed digoxin serum concentrations were 0.67, 0.83, and 1.05 ng/mL after 1, 2, and 5 days after the initiation of digoxin therapy, respectively. Although the serum digoxin concentrations reached the target range, the FHR did not improve. Therefore, digoxin was discontinued, and oral flecainide therapy was started. The FHR adjusted to the normal range within 2 days from changing treatment and remained stable. TDM of digoxin along with the monitoring of clinical responses can give valuable information for decision-making during the treatment FT.

The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The noncompartmental method was used for the determination of PK parameters. Change of mean pH and proportion (%) of time of gastric pH above 4.0 were estimated. The poor metabolizer (PM) group had the lowest metabolic ratio and exhibited the highest area under the curve (AUC) for omeprazole among the CYP2C19 phenotype groups. The PM group showed the greatest change of mean pH and the highest % time of gastric pH above 4.0. The relationship between AUC of omeprazole and % time of gastric pH above 4.0 was confirmed. The study demonstrates that CYP2C19*2 and *3 influence the PKs and PDs of omeprazole in Korean healthy volunteers. Clinical trial registry at the U.S. National Institutes of Health (https://clinicaltrials.gov), number NCT02299687.
Area Under Curve ; Chromatography, Liquid ; Cytochrome P-450 CYP2C19* ; Genotype ; Healthy Volunteers* ; Hydrogen-Ion Concentration ; Methods ; National Institutes of Health (U.S.) ; Omeprazole* ; Phenotype ; Plasma ; Polymorphism, Genetic* ; Polymorphism, Single Nucleotide ; Tandem Mass Spectrometry ; Volunteers