Iodine intake from brown seaweed and the related nutritional risk assessment in Koreans.

BACKGROUND/OBJECTIVES: Although iodine is essential for thyroid hormone production and controls many metabolic processes, there are few reports on the iodine intake of the population because of the scarcity of information on the iodine content in food. This study estimated the iodine intake of Koreans from brown seaweed, the major source of iodine in nature. SUBJECTS/METHODS: The dietary intake data from the recent Korea National Health and Nutrition Examination Survey (2016-2021) and the iodine content in brown seaweed were used for the estimation. Nationwide brown seaweed samples were collected and prepared using the representative preparation/cooking methods in the Koreans' diet before iodine analysis by alkaline digestion followed by inductively coupled plasma mass spectrometry. RESULTS: The mean (± SE) iodine intake from sea mustard was 96.01 ± 2.36 µg/day in the Korean population. Although the iodine content in kelp was approximately seven times higher than that in sea mustard, the mean iodine intake from kelp (except broth) was similar to that of sea mustard, 115.58 ± 7.71 µg/day, whereas that from kelp broth was 347.57 ± 10.03 µg/day. The overall mean iodine intake from brown seaweed was 559.16 ± 13.15 µg/day, well over the Recommended Nutrient Intake of iodine for Koreans. Nevertheless, the median intake was zero because only 37.6% of the population consumed brown seaweed on the survey date, suggesting that Koreans do not consume brown seaweed daily. CONCLUSION: The distribution of the usual intake of iodine from brown seaweed in Koreans would be much tighter, resulting in a lower proportion of people exceeding the tolerable upper intake levels and possibly a lower mean intake than this study presented. Further study evaluating the iodine nutriture of Koreans based on the usual intake is warranted. Nevertheless, this study adds to the few reports on the iodine nutriture of Koreans.

Progress on sodium reduction in South Korea.

INTRODUCTION: High dietary sodium is a leading contributor to hypertension, and hypertension is the leading underlying cause of death globally. There is a robust body of evidence supporting the health benefits of sodium reduction. Sodium intake in South Korea is high, with about half the population consuming >4000 mg/day, twice the recommended upper limit. METHODS: In 2012, South Korea implemented its National Plan to Reduce Sodium Intake, with a goal of reducing population sodium consumption by 20%, to 3900 mg/day, by 2020. The plan included five key components: (1) a consumer awareness campaign designed to change food consumption behaviours; (2) increased availability of low-sodium foods at schools and worksites; (3) increased availability of low-sodium meals in restaurants; (4) voluntary reformulation of processed foods to lower sodium content; and (5) development of low-sodium recipes for food prepared at home. Monitoring and evaluation included tracking sodium intake and sources of dietary sodium using the Korea National Health and Nutrition Examination Survey. RESULTS: By 2014, South Korea had reduced dietary sodium consumption among adults by 23.7% compared to a survey conducted in 2010 prior to implementation of a nationwide salt reduction campaign that used this comprehensive, multipronged approach. The reductions in sodium intake were accompanied by reductions in population blood pressure and hypertension prevalence. Although causal associations between the sodium reduction programme and reduced sodium intake cannot be made, the declines occurred with the introduction of the programme. CONCLUSION: Multicomponent interventions have great potential to reduce population sodium intake. Lessons learnt from South Korea could be applied to other countries and are likely very relevant to other Asian countries with similar food sources and consumption profiles.

Prediction of Methionine and Homocysteine levels in Zucker diabetic fatty (ZDF) rats as a T2DM animal model after consumption of a Methionine-rich diet.

BACKGROUND: Although alterations in the methionine metabolism cycle (MMC) have been associated with vascular complications of diabetes, there have not been consistent results about the levels of methionine and homocysteine in type 2 diabetes mellitus (T2DM). The aim of the current study was to predict changes in plasma methionine and homocysteine concentrations after simulated consumption of methionine-rich foods, following the development of a mathematical model for MMC in Zucker Diabetic Fatty (ZDF) rats, as a representative T2DM animal model. METHOD: The model building and simulation were performed using NONMEM® (ver. 7.3.0) assisted by Perl-Speaks-NONMEM (PsN, ver. 4.3.0). Model parameters were derived using first-order conditional estimation method with interactions permitted among the parameters (FOCE-INTER). NCA was conducted using Phoenix (ver. 6.4.0). For all tests, we considered a P-value < 0.05 to reflect statistical significance. RESULTS: Our model featured seven compartments that considered all parts of the cycle by applying non-linear mixed effects model. Conversion of S-adenosyl-L-homocysteine (SAH) to homocysteine increased and the metabolism of homocysteine was reduced under diabetic conditions, and consequently homocysteine accumulated in the elimination phase.Using our model, we performed simulations to compare the changes in plasma methionine and homocysteine concentrations between ZDF and normal rats, by multiple administrations of the methionine-rich diet of 1 mmol/kg, daily for 60 days. The levels of methionine and homocysteine were elevated approximately two- and three-fold, respectively, in ZDF rats, while there were no changes observed in the normal control rats. CONCLUSION: These results can be interpreted to mean that both methionine and homocysteine will accumulate in patients with T2DM, who regularly consume high-methionine foods.

A mechanism-based pharmacokinetic model of fenofibrate for explaining increased drug absorption after food consumption.

BACKGROUND: Oral administration of drugs is convenient and shows good compliance but it can be affected by many factors in the gastrointestinal (GI) system. Consumption of food is one of the major factors affecting the GI system and consequently the absorption of drugs. The aim of this study was to develop a mechanistic GI absorption model for explaining the effect of food on fenofibrate pharmacokinetics (PK), focusing on the food type and calorie content. METHODS: Clinical data from a fenofibrate PK study involving three different conditions (fasting, standard meals and high-fat meals) were used. The model was developed by nonlinear mixed effect modeling method. Both linear and nonlinear effects were evaluated to explain the impact of food intake on drug absorption. Similarly, to explain changes in gastric emptying time for the drug due to food effects was evaluated. RESULTS: The gastric emptying rate increased by 61.7% during the first 6.94 h after food consumption. Increased calories in the duodenum increased the absorption rate constant of the drug in fed conditions (standard meal = 16.5%, high-fat meal = 21.8%) compared with fasted condition. The final model displayed good prediction power and precision. CONCLUSIONS: A mechanistic GI absorption model for quantitatively evaluating the effects of food on fenofibrate absorption was successfully developed, and acceptable parameters were obtained. The mechanism-based PK model of fenofibrate can quantify the effects of food on drug absorption by food type and calorie content.

Performance comparison of first-order conditional estimation with interaction and Bayesian estimation methods for estimating the population parameters and its distribution from data sets with a low number of subjects.

BACKGROUND: Exploratory preclinical, as well as clinical trials, may involve a small number of patients, making it difficult to calculate and analyze the pharmacokinetic (PK) parameters, especially if the PK parameters show very high inter-individual variability (IIV). In this study, the performance of a classical first-order conditional estimation with interaction (FOCE-I) and expectation maximization (EM)-based Markov chain Monte Carlo Bayesian (BAYES) estimation methods were compared for estimating the population parameters and its distribution from data sets having a low number of subjects. METHODS: In this study, 100 data sets were simulated with eight sampling points for each subject and with six different levels of IIV (5%, 10%, 20%, 30%, 50%, and 80%) in their PK parameter distribution. A stochastic simulation and estimation (SSE) study was performed to simultaneously simulate data sets and estimate the parameters using four different methods: FOCE-I only, BAYES(C) (FOCE-I and BAYES composite method), BAYES(F) (BAYES with all true initial parameters and fixed ω 2 ), and BAYES only. Relative root mean squared error (rRMSE) and relative estimation error (REE) were used to analyze the differences between true and estimated values. A case study was performed with a clinical data of theophylline available in NONMEM distribution media. NONMEM software assisted by Pirana, PsN, and Xpose was used to estimate population PK parameters, and R program was used to analyze and plot the results. RESULTS: The rRMSE and REE values of all parameter (fixed effect and random effect) estimates showed that all four methods performed equally at the lower IIV levels, while the FOCE-I method performed better than other EM-based methods at higher IIV levels (greater than 30%). In general, estimates of random-effect parameters showed significant bias and imprecision, irrespective of the estimation method used and the level of IIV. Similar performance of the estimation methods was observed with theophylline dataset. CONCLUSIONS: The classical FOCE-I method appeared to estimate the PK parameters more reliably than the BAYES method when using a simple model and data containing only a few subjects. EM-based estimation methods can be considered for adapting to the specific needs of a modeling project at later steps of modeling.

Creating a school nutrition environment index and pilot testing it in elementary and middle schools in urban South Korea.

BACKGROUND/OBJECTIVES: The role of a school's nutrition environment in explaining students' eating behaviors and weight status has not been examined in an Asian setting. The purpose of this study was to create a school nutrition environment index and to pilot test the index in elementary and middle schools in urban South Korea. SUBJECTS/METHODS: This study used a mixed-methods approach. Environment assessment tools were developed based on formative research, which comprised literature reviews, in-depth interviews, and focus group discussions. Key elements from the formative research were included in the assessment tool, which consisted of a structured survey questionnaire for school dietitians. Fifteen school dietitians from 7 elementary and 8 middle schools in Seoul completed the questionnaire. RESULTS: The formative research revealed four main sections that guided a summary index to assess a school's nutrition environment: resource availability, education and programs, dietitians' perceptions and characteristics, and school lunch menu. Based on the literature reviews and interviews, an index scoring system was developed. The total possible score from the combined four index sections was 40 points. From the 15 schools participating in the pilot survey, the mean school nutrition-environment index was 22.5 (standard deviation ± 3.2; range 17-28). The majority of the schools did not offer classroom-based nutrition education or nutrition counseling for students and parents. The popular modes of nutrition education were school websites, posters, and newsletters. CONCLUSIONS: This paper illustrates the process used to develop an instrument to assess a school's nutrition environment. Moreover, it presents the steps used to develop a scoring system for creation of a school nutrition environment index. As pilot testing indicated the total index score has some variation across schools, we suggest applying this instrument in future studies involving a larger number of schools. Future studies with larger samples will allow investigation of the validity and reliability of this newly developed tool.

Development of a LC-MS/MS method for the determination of CKD-712 in rat plasma: Application to a pharmacokinetic study in rats.

CKD-712 is a potential treatment for sepsis, as it exhibits protective effects against lipopolysaccharide-mediated platelet aggregation, inducible nitric oxide synthase expression, and cecum-ligation puncture-induced septic mortality in mice. In this study, we develop a rapid and sensitive LC-MS/MS method for determining CKD-712 in rat plasma. CKD-712 and papaverine hydrochloride (an internal standard) were analyzed using an LC-MS/MS system consisting of an Agilent HPLC system (HP-1100) equipped with an Atlantis HILIC Silica (2.1×50mm, 3µm) column and a API 4000 (Applied Biosystems/MDS Sciex, USA) in a positive ESI mode. We utilized multiple reaction monitoring (MRM) at m/z transitions of 306.2-164.0 to analyze CKD-712, and 340.3-202.1 m/z for IS, with a mobile phase of acetonitrile (0.025% trifluoroacetic acid):20mM ammonium acetate (94:6, v/v) at a flow rate of 0.25mL/min. The lower limit of quantification (LLOQ) was 5ng/mL, with a linearity ranging from 5 to 1000ng/mL (r>0.999). Validation parameters including specificity, precision, accuracy, matrix effect, recovery, dilution effect and stability results were well within acceptance criteria, and applied successfully on a pharmacokinetic study in rats.

BSA and ABCB1 polymorphism affect the pharmacokinetics of sunitinib and its active metabolite in Asian mRCC patients receiving an attenuated sunitinib dosing regimen.

PURPOSE: An attenuated dosing (AD) sunitinib regimen of 37.5 mg daily has been suggested to reduce the toxicity reported with the standard dosing regimen to metastatic renal cell carcinoma (mRCC) patients. The aim of this study was to characterize the population pharmacokinetic (PK) properties of sunitinib and SU12662, the active metabolite, in patients receiving the AD regimen and to ascertain significant covariates influencing PK parameters. METHODS: Thirty-one mRCC patients receiving AD sunitinib regimen were included. Plasma samples were collected on day 29 of each treatment cycle after the start of the therapy. Nonlinear mixed-effects modeling was applied to estimate the population PK properties of sunitinib and SU12662 as well as the effect of covariates on PK parameters. Monte Carlo simulation was also performed to predict the total trough level (TTL) of sunitinib and SU12662. RESULTS: Sunitinib population means for CL/F and V d /F central were 13.8 L/h and 1720 L, respectively. SU12662 population means for CL/F and V d /F were 42.1 L/h and 1410 L, respectively. Body surface area (BSA) and ABCB1 polymorphism significantly influenced the CL/F variability of sunitinib: CL/F parent = 13.8 × exp((BSA - 1.75) × 2.08 + (ABCB1 genotype - 0.67) × 0.61), ABCB1-0: wild genotype, 1: mutant genotype. The effect size of ABCB1 mutant genotype and BSA greater than 1.75 m(2) in relation to sunitinib clearance was 31.14 % (p = 0.006) and 22.11 % (p = 0.011), respectively, relative to the reference group. CONCLUSIONS: Adjusting doses of sunitinib according to BSA and ABCB1 polymorphism in Asian mRCC patients may be recommended for sufficient attainment of a target TTL of sunitinib and its metabolite.

Inhibition of Cytochrome P450 by Propolis in Human Liver Microsomes.

Although propolis is one of the most popular functional foods for human health, there have been no comprehensive studies of herb-drug interactions through cytochrome P450 (CYP) inhibition. The purpose of this study was to determine the inhibitory effects of propolis on the activities of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 using pooled human liver microsomes (HLMs). Propolis inhibited CYP1A2, CYP2E1 and CYP2C19 with an IC50 value of 6.9, 16.8, and 43.1 µg/mL, respectively, whereas CYP2A6, 2B6, 2C9, 2D6, and 3A4 were unaffected. Based on half-maximal inhibitory concentration shifts between microsomes incubated with and without nicotinamide adenine dinucleotide phosphate, propolis-induced CYP1A2, CYP2C19, and CYP2E1 inhibition was metabolism-independent. To evaluate the interaction potential between propolis and therapeutic drugs, the effects of propolis on metabolism of duloxetine, a serotonin-norepinephrine reuptake inhibitor, were determined in HLMs. CYP1A2 and CYP2D6 are involved in hydroxylation of duloxetine to 4-hydroxy duloxetine, the major metabolite, which was decreased following propolis addition in HLMs. These results raise the possibility of interactions between propolis and therapeutic drugs metabolized by CYP1A2.

Michaelis-Menten elimination kinetics of etanercept, rheumatoid arthritis biologics, after intravenous and subcutaneous administration in rats.

Etanercept was approved by the Food and Drug Administration (FDA) in 2010 as a biologic agent for the treatment of rheumatoid arthritis (RA). The aim of the study was to investigate the pharmacokinetic properties of etanercept after intravenous and subcutaneous injection in rats. The plasma concentration of etanercept was determined using an enzyme-linked immunosorbent assay (ELISA). Intravenous and subcutaneous administration of 2 mg/kg of etanercept to rats showed that etanercept was slowly absorbed (time to reach the peak drug concentration [T max] = 1.60 days, bioavailability [F] = 47.18 %) and slowly eliminated (half-life [t 1/2], 2.33 days after intravenous administration and 3.31 days after subcutaneous administration). The area under the curve values on day 13 (AUC13day) were 121.25 ± 14.37 and 48.56 ± 6.78 µg day/mL after intravenous and subcutaneous administration, respectively. A two-compartment model with Michaelis-Menten elimination kinetics (V max = 94.28 µg/day; K m = 10.88 µg/mL) was used to describe the pharmacokinetic profile of etanercept. Our results describe the pharmacokinetic profile of etanercept, and these results could be used for the development of etanercept biosimilars.

A novel HPLC-MS/MS method for the simultaneous determination of astemizole and its major metabolite in dog or monkey plasma and application to pharmacokinetics.

Astemizole (AST), a second-generation antihistamine, is metabolized to desmethyl astemizole (DEA), and although it has been removed from the market for inducing QT interval prolongation, it has reemerged as a potential anticancer and antimalarial agent. This report describes a novel high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneously determining the concentrations of AST and DEA in beagle dog and cynomolgus monkey plasma with simple preparation method and short retention time. Prior to HPLC analyses, the plasma samples were extracted with simple liquid-liquid extraction method. The isocratic mobile phase was 0.025% trifluoroacetic acid (TFA dissolved in acetonitrile) and 20 mM ammonium acetate (94:6) at a flow rate of 0.25 mL/min and diphenhydramine used as internal standard. In MS/MS analyses, precursor ions of the analytes were optimized as protonated molecular ions: [M+H](+). The lower limit of quantification of astemizole was 2.5 ng/mL in both species and desmethyl astemizole were 7.5 ng/mL and 10 ng/mL in dog and monkey plasma, respectively. The accuracy, precision, and stability of the method were in accordance with FDA guidelines for the validation of bioanalytical methods. Finally this validated method was successfully applied to a pharmacokinetic study in dogs and monkeys after oral administration of 10 mg/kg AST.

Determination of Matrine in Rat Plasma after Oral Administration of Novel Korean Herbal Medicine KIOM-MA128 and Application of PK.

KIOM-MA128 is a novel Korean herbal medicine with antiatopic, anti-inflammatory, and antiasthmatic effects. Matrine is thought to be a potential chemical marker of KIOM-MA128, but pharmacokinetic studies on KIOM-MA128 had not been performed. This study describes a simple and rapid method using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to determine the concentration of matrine in rats plasma after administration of KIOM-MA128. The isocratic mobile phase consisted of methanol and distilled water, and the flow rate was 0.15 mL/min. The accuracy and precision of the assay, as well as stability tests, were performed in accordance with FDA regulations for the validation of bioanalytical methods. The half-life and T max of matrine after administration of KIOM-MA128 were 4.29 ± 2.20 h and 1.8 ± 1.23 h, respectively. C max and AUCinf of matrine after administration of KIOM-MA128 at 4 g/kg and 8 g/kg were 595.10 ± 182.91 ng/mL, 5336.77 ± 1503.84 ng/mL·h and 850.46 ± 120 ng/mL, 9583.10 ± 888.92 ng/mL·h, respectively. The validated method was successfully applied to a pharmacokinetic study in rats after oral administration of KIOM-MA128.

Development of QTc prolongation model incorporating circadian rhythm using harmonic model.

1. QT prolongation is one of the major safety tests used in the development of a new drug. The ICH guidelines for the evaluation of QT prolongation recommend the use of the in vitro hERG assay and the in vivo telemetry test. However, QT intervals change under normal conditions due to circadian rhythm and can affect the results of the tests. In this study, we developed a PK/PD model to describe the QT interval after the administration of astemizole allowing for the normal changes by circadian rhythm. 2. The typical PK parameters of absorption rate constant (ka), volume of distribution (Vc and Vm), metabolism (km), and elimination rate constant (kel and kel-m) were 0.49 h(-1), 4950 L, 20 L, 0.0127 h(-1), 0.0095 h(-1), and 0.95 h(-1), respectively. The final PK/PD model was the biophase model with the modified harmonic model. The typical PK/PD parameters, base QTc interval (QT0), amplitude (T1, T3), period of QTc interval changing (T2, T4), and EC50 were 233 ms, 3.31, 1.5, -9.24 h, 1.85 h, and 0.81 ng/ml, respectively. 3. The PK/PD model to explain the changes of the QT interval that allows normal changes in the circadian rhythm after the administration of astemizole was developed successfully. This final model can be applied to the development of a human model.

Quantitative determination of amisulpride in rat plasma by HPLC-MS/MS.

Amisulpride, a selective antagonist of D2 and D3 dopamine receptors, is used as an antipsychotic drug. In this study, we reported a sensitive LC-MS/MS method for determining amisulpride concentrations in rat plasma, and a preclinical pharmacokinetic study in the rat. After a simple protein precipitation with acetonitrile containing methaqualone as an internal standard, the analytes were separated on a reversed-phase column with a mobile phase of 0.2 % aqueous formic acid and acetonitrile (3:7, v/v). The accuracy and precision of the assay were in accordance with FDA guidance for the validation of bioanalytical methods. This analytical method was used successfully to characterize the time course of the plasma concentration of amisulpride following oral administration of a single 10 mg/kg dose in rats.

Absolute bioavailability and metabolism of aceclofenac in rats.

Aceclofenac is one of the most popular analgesic and anti-inflammatory drugs used for the relief of pain, rheumatoid arthritis, and osteoarthritis. To date, no intravenous preparation of aceclofenac has been developed because of its poor water solubility. In this study, to investigate its absolute bioavailability and metabolism in rats, aceclofenac was dissolved in a sterile aqueous solution containing urea (20 %) and trisodium citrate (10 %), and administered via oral (20 mg/kg) and intravenous (10 mg/kg) routes. Blood samples were taken serially, and aceclofenac and its three major metabolites (4'-hydroxydiclofenac, 4'-hydroxyaceclofenac, and diclofenac) were measured by HPLC-MS/MS. The absolute oral bioavailability of aceclofenac was approximately 15 %. Diclofenac and 4'-hydroxydiclofenac were the main metabolites in rats, in contrast to 4'-hydroxyaceclofenac in humans. The low bioavailability of aceclofenac is likely due to extensive metabolism, and bioavailability may be even lower if the drug were administered as a tablet, considering its low water solubility. This study provides complete time profiles of the plasma concentrations of aceclofenac and its metabolites in rats and highlights the difference in drug metabolism between rats and humans.

Population pharmacokinetic and pharmacodynamic modeling of transformed binary effect data of triflusal in healthy Korean male volunteers: a randomized, open-label, multiple dose, crossover study.

BACKGROUND: Triflusal is a drug that inhibits platelet aggregation. In this study we investigated the dose-exposure-response relationship of a triflusal formulation by population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of its main active metabolite, hydroxy-4-(trifluoromethyl) benzoic acid (HTB). METHODS: This study was a randomized, open-label, multiple-dose, two-period, two-treatment, comparative crossover design. All volunteers received a single oral loading dose of 900 mg of triflusal on Day 1, followed by a dose of 600 mg/day from Day 2 to 9. Using data from 34 healthy volunteers, 476 HTB plasma concentration data points and 340 platelet aggregation data points were used to construct PK and PD models respectively using NONMEM (version 6.2). As the PD endpoint was qualitative, we implemented binary analysis of 'inhibition' and 'non-inhibition' rather than using the actual value of the test. The final PK-PD model was evaluated using a visual predictive check (VPC) and bootstrap. RESULTS: The time-concentration profile of HTB over the entire dosing period was described by a one-compartment model with a first-order formation rate constant for HTB. Weight was selected as a covariate for clearance and volume of triflusal, respectively. The structure and the population estimates for triflusal PK were as follows: oral clearance (CL/F) = 0.2 · (weight/71.65)(0.845) L/h, oral volume of distribution (V/F) = 8.3 · (weight/71.65) L, and k f = 0.341 h(-1). A sigmoid relationship between triflusal concentration and the probability of significant inhibition with shape factor was chosen as the final PD model. No time delay between concentration and response was identified. The final structure between predicted concentration (C(y)(pred,ij) and the probability of inhibition of platelet aggregation (IPA) relationship was as follows: Probability of IPA = C(19)(pred,ij)/((84.9)(19) µg/mL + C(19)(pred,ij)). Thus, we concluded this relationship is more like quantal concentration-response relationship. The current dosing regimen was considered to be efficacious based on the EC 50 estimate of 84.9 µg/mL obtained in this study. CONCLUSIONS: A PK and binary probability PD model of triflusal was successfully developed for Korean healthy volunteers. The model may be used to further prediction inhibition of platelet aggregation by triflusal. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0001299 (Registered December 5, 2014).

Early adulthood: an overlooked age group in national sodium reduction initiatives in South Korea.

BACKGROUND/OBJECTIVES: South Korean's sodium consumption level is more than twice the upper limit level suggested by the WHO. Steep increases in the prevalence of hypertension and cardiovascular disease in Korea necessitate more effective sodium reduction programs. This study was conducted in order to compare sodium intake-related eating behaviors and key psychosocial factors according to age group and gender. SUBJECTS/METHODS: Using an online survey, a total of 1,564 adults (20-59 years old) considered to be geographically representative of South Korea were recruited and surveyed. The major outcomes were perceived behaviors, knowledge, intentions, and self-efficacy related to sodium intake. RESULTS: The results show that perceived behavior and level of self-efficacy related to low sodium consumption differed by age and gender. Female participants showed better behavior and intention towards low sodium intake than male counterparts. Young participants in their 20s showed the lowest intention to change their current sodium intake as well as lowest self-efficacy measures. CONCLUSIONS: Future sodium reduction interventions should be developed with tailored messages targeting different age and gender groups. Specifically, interventions can be planned and implemented at the college level or for workers in their early career to increase their intention and self-efficacy as a means of preventing future health complications associated with high sodium intake.

Simultaneous determination of 7-O-succinyl macrolactin A and its active major metabolite, macrolactin A in dog plasma using high-performance liquid chromatography with UV detection.

We developed a method for the simultaneous quantification of 7-O-succinyl macrolactin A and its active metabolite, macrolactin A, in dog plasma. After protein precipitation with acetonitrile including flufenamic acid as an internal standard, 7-O-succinyl macrolactin A, macrolactin A, and flufenamic acid were chromatographed on a reverse-phase C18 analytical column. The mobile phase, consisting of 20 mM acetate buffer and acetonitrile, was eluted using a gradient program at 1 mL/min, and the UV absorbance was measured at 230 nm. The retention times of 7-O-succinyl macrolactin A, flufenamic acid, and macrolactin A were 3.4, 4.8, and 6.9 min, respectively. The coefficient of variation in the assay precision for both substances was less than 6%, and the accuracy ranged from 96 to 105%. This method was used to measure the concentrations of 7-O-succinyl macrolactin A and macrolactin A in dog plasma following an intravenous administration of a single dose (25 mg/kg) of 7-O-succinyl macrolactin A salt.

Inhibition of cytochrome P450 by ethambutol in human liver microsomes.

Although cytochrome P450 inhibition is the major drug-drug interaction (DDI) mechanism in clinical pharmacotherapy, DDI of a number of well-established drugs have not been investigated. Rifampicin, isoniazid, pyrazinamide and ethambutol combination therapy inhibits clearance of theophylline in patients with tuberculosis. We determined the inhibitory effects of ethambutol on the activities of nine CYP isoforms including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 in pooled human liver microsomes (HLM). As measured by liquid chromatography-electrospray ionization tandem mass spectrometry, ethambutol exhibited strong inhibitory potential against CYP1A2 and CYP2E1, moderate against CYP2C19 and CYP2D6 and weak against CYP2A6, CYP2C9 and CYP3A4, based on the IC50 values. The K(i) value of ethambutol for CYP1A2 was 1.4 µM and for CYP2E1 was 2.9 µM. Inhibition of CYP1A2 and CYP2E1 was not increased by preincubation with ethambutol and ß-nicotinamideadenine dinucleotide phosphate (NADPH), suggesting that the ethambutol-induced CYP inhibition may not be metabolism-dependent. Kinetic analysis showed that the inhibition of CYP1A2 and CYP2E1 by ethambutol was best fit to a competitive inhibition model. Formation of 1-methylxanthene and 1,3-dimethyluric acid from theophylline in HLM was decreased to 47% and 36%, respectively, by 3.0 µM ethambutol, which is comparable to its IC50 value against CYP1A2. Considering its maximal plasma concentrations of ~10 µM and long half-life of ~22 h, our findings raise the possibility that ethambutol causes significant DDIs in clinical situations with drugs with narrow therapeutic index, such as theophylline, in clinical situations.

Development of a population pharmacokinetic model to describe olmesartan medoxomil/ hydrochlorothiazide (20/12.5 mg) FDC tablet in male healthy South Korean subjects.

AIM: The objective of the present study was to develop population pharmacokinetic models for olmesartan medoxomil and hydrochlorothiazide and to investigate the influence of demographic factors on these population pharmacokinetics. METHODS: Plasma concentrations of olmesartan medoxomil and hydrochlorothiazide were measured in 41 healthy volunteers enrolled in our bioequivalence study by LC-MS/MS following oral administration of an olmesartan medoxomil/hydrochlorothiazide (20/12.5 mg) fixed-dose combination tablet. This data and covariates were subjected to nonlinear mixed-effect modeling analysis using the NONMEM software. Evaluation featured a visual predicted check and bootstrapping. RESULTS: The distributions of olmesartan medoxomil and hydrochlorothiazide were best fitted using a two-compartment model with no lag time and first-order elimination. When analyzing hydrochlorothiazide kinetics, we found that TCHO and CL/F were correlated, while. HB and Ka influenced olmesartan medoxomil modeling. All evaluations indicated that the pharmacokinetic profiles of olmesartan medoxomil and hydrochlorothiazide were adequately described using our PPK model. CONCLUSIONS: This study indicates that demographic factors influence the inter-individual variability in the disposition of the combination drug, and it might be more useful to apply it to the PK of olmesartan medoxomil/hydrochlorothiazide (20/12.5 mg) FDC tablets administered to patients with hypertension. *These two authors contributed equally to this work.