Evaluation of the transporter-mediated herb-drug interaction potential of DA-9801, a standardized dioscorea extract for diabetic neuropathy, in human in vitro and rat in vivo

BACKGROUND: Drug transporters play important roles in the absorption, distribution, and elimination of drugs and thereby, modulate drug efficacy and toxicity. With a growing use of poly pharmacy, concurrent administration of herbal extracts that modulate transporter activities with drugs can cause serious adverse reactions. Therefore, prediction and evaluation of drug-drug interaction potential is important in the clinic and in the drug development process. DA-9801, comprising a mixed extract of Dioscoreae rhizoma and Dioscorea nipponica Makino, is a new standardized extract currently being evaluated for diabetic peripheral neuropathy in a phase II clinical study. METHOD: The inhibitory effects of DA-9801 on the transport functions of organic cation transporter (OCT)1, OCT2, organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) were investigated in HEK293 or LLC-PK1 cells. The effects of DA-9801 on the pharmacokinetics of relevant substrate drugs of these transporters were also examined in vivo in rats. RESULTS: DA-9801 inhibited the in vitro transport activities of OCT1, OCT2, OAT3, and OATP1B1, with IC(50) values of 106, 174, 48.1, and 273 μg/mL, respectively, while the other transporters were not inhibited by 300 μg/mL DA-9801. To investigate whether this inhibitory effect of DA-9801 on OCT1, OCT2, and OAT3 could change the pharmacokinetics of their substrates in vivo, we measured the pharmacokinetics of cimetidine, a substrate for OCT1, OCT2, and OAT3, and of furosemide, a substrate for OAT1 and OAT3, by co-administration of DA-9801 at a single oral dose of 1,000 mg/kg. Pre-dose of DA-9801 5 min or 2 h prior to cimetidine administration decreased the C(max) of cimetidine in rats. However, DA-9801 did not affect the elimination parameters such as half-life, clearance, or amount excreted in the urine, suggesting that it did not inhibit elimination process of cimetidine, which is governed by OCT1, OCT2, and OAT3. Moreover, DA-9801 did not affect the pharmacokinetic characteristics of furosemide, as evidenced by its unchanged pharmacokinetic parameters. CONCLUSION: Inhibitory effects of DA-9801 on OCT1, OCT2, and OAT3 observed in vitro may not necessarily translate into in vivo herb-drug interactions in rats even at its maximum effective dose

Comparison of the Efficacy of Glimepiride, Metformin, and Rosiglitazone Monotherapy in Korean Drug-Naïve Type 2 Diabetic Patients: The Practical Evidence of Antidiabetic Monotherapy Study

BackgroundAlthough many anti-diabetic drugs have been used to control hyperglycemia for decades, the efficacy of commonly-used oral glucose-lowering agents in Korean type 2 diabetic patients has yet to be clearly demonstrated.MethodsWe evaluated the efficacy of glimepiride, metformin, and rosiglitazone as initial treatment for drug-naïve type 2 diabetes mellitus patients in a 48-week, double-blind, randomized controlled study that included 349 Korean patients. Our primary goal was to determine the change in HbA1c levels from baseline to end point. Our secondary goal was to evaluate changes in fasting plasma glucose (FPG) levels, body weight, frequency of adverse events, and the proportion of participants achieving target HbA1c levels.ResultsHbA1c levels decreased from 7.8% to 6.9% in the glimepiride group (P<0.001), from 7.9% to 7.0% in the metformin group (P<0.001), and from 7.8% to 7.0% (P<0.001) in the rosiglitazone group. Glimepiride and rosiglitazone significantly increased body weight and metformin reduced body weight during the study period. Symptomatic hypoglycemia was more frequent in the glimepiride group and diarrhea was more frequent in the metformin group.ConclusionThe efficacy of glimepiride, metformin, and rosiglitazone as antidiabetic monotherapies in drug-naïve Korean type 2 diabetic patients was similar in the three groups, with no statistical difference. This study is the first randomized controlled trial to evaluate the efficacy of commonly-used oral hypoglycemic agents in Korean type 2 diabetic patients. An additional subgroup analysis is recommended to obtain more detailed information

Seasonal variation, phase distribution, and source identification of atmospheric polycyclic aromatic hydrocarbons at a semi-rural site in Ulsan, South Korea

Polycyclic aromatic hydrocarbons (PAHs) in gaseous and particulate phases (n = 188) were collected in Ulsan, South Korea, over a period of one year (June 2013-May 2014) to understand the seasonal variation and phase distribution of PAHs as well as to identify the seasonal PAH emission sources. The target compounds were the 16 US-EPA priority PAHs, with the exception of naphthalene, acenaphthylene, and acenaphthene. Winter and spring had the highest and lowest PAH concentrations, respectively. The mean of the Sigma(13) PAHs in the gaseous phase (4.11 ng/m(3)) was higher than that in the particulate phase (2.55 ng/m(3)). Fractions of the gaseous or 3- and 4-ring PAHs (i.e., Flu, Phe, and Ant) were high in summer, and those of the particulate or 5- and 6-ring PAHs (i.e., BkF, BaP, Ind, DahA, and BghiP) increased in winter. Gas/particle partitioning models also demonstrated the increased contributions of the particulate PAHs in spring and winter. Source identification of PAHs was undertaken using diagnostic ratios, principal component analysis, and positive matrix factorization. The results indicated that pyrogenic sources (e.g., coal combustion) were dominant in winter. Other types of pyrogenic (e.g., industrial fuel combustion) and petrogenic sources were the main PAH sources in summer and autumn. The influence of both sources, especially in summer, might be due to seasonal winds transporting PAHs from the industrial areas. Two types of pyrogenic sources, diesel and coal combustion, were identified as the main PAH sources in spring. This study clearly demonstrates a source-receptor relation of PAHs at a semi-rural site in a heavily industrialized city. (C) 2018 Elsevier Ltd. All rights reserved

Seasonal variation and emission sources of polycyclic aromatic hydrocarbons at a rural site in Ulsan

Polycyclic aromatic hydrocarbons (PAHs) in gaseous and particulate phases (n = 188) were collected in Ulsan for four seasons (June 2013&amp;#8211;May 2014) to understand the PAH seasonal variation and emission sources. The target compounds were 16 US-EPA PAHs, except for napthelane, acenapthylene, and acenapthene. Diagnostic ratios, principal component analysis, and positive matrix factorization were applied to identify seasonal emission sources of PAHs. The highest and lowest PAH concentrations were observed in winter and spring, respectively. In addition, concentration of the gaseous phase (4.11 ng/m3) was approximately two times higher than that of the particulate phase (2.55ng/m3). Contributions of the gaseous or 3-4 ring PAHs (i.e., Flu, Phe, and Ant) were dominant in summer, whereas those of the particulate or 5-6 ring PAHs (i.e., BkF, BaP, Ind, DahA, BghiP) were higher in winter. For source identification, the main PAH source in winter was coal combustion. Autumn and spring shared the similar PAH emission sources, including exhaust from transportation activities and biomass burning. Summer also had mixed PAH sources, including engine emissions and pyrogenic or coke ovens, originated from the industrial areas of Ulsan and affected the sampling site by the primary seasonal wind