Hyo-In Yun

Pharmacokinetics of mirtazapine and its main metabolites in Beagle dogs: A pilot study

Mirtazapine (MRT) is a human antidepressant drug mainly metabolised by the cytochrome P450 enzyme system to 8-OH mirtazapine (8-OH) and dimetilmirtazapine (DMR). The drug is usually administered to dogs with anorexia according to doses extrapolated from humans, although it could also have applications as an antidepressant and analgesic in this species. The aim of this study was to assess the pharmacokinetics of MRT and its metabolites, DMT and 8-OH. Six healthy male Beagle dogs were administered MRT orally (20 mg/dog) and plasma MRT and metabolite concentrations were evaluated by high performance liquid chromatography with fluorescence detection. The pharmacokinetic profiles of MRT and DMR were similar (detected from 0.25 up to 10 h), while 8-OH (detected from 0.50 up to 10 h) attained the highest concentrations. The mean half-life of MRT was 6.17 h with a clearance of 1193 mL/h/kg. The study showed that MRT has a different pharmacokinetic profile in the dog compared to other species.

Determination of roxithromycin residues in the flounder muscle with electrospray liquid chromatography-mass spectrometry.

A highly sensitive and specific method for the determination of roxithromycin in the flounder muscle by LC-MS was developed and validated. A dichloromethane extract of the sample was separated on C18 reversed-phase column with acetonitrile-50 mM ammonium acetate (80:20, v/v) as the mobile phase and analyzed by LC-MS via atmospheric pressure ionization/electrospray ionization interface. The limit of detection and limit of quantitation were 0.01 and 0.1 ng/g, respectively. Mean recoveries from spiked muscles were 81.1% (ranged from 71.0 to 90.3%) for roxithromycin. The method has been successfully applied to determine roxithromycin in the flounder muscle.

Sensitive liquid chromatographic–mass spectrometric assay for norfloxacin in poultry tissue

A highly sensitive and specific method for the determination of norfloxacin in poultry tissues by LC-MS was developed and validated. An extract of the sample was separated on a C(18) reversed-phase column and analyzed by LC-MS. The mobile phase was gradiently flowed with 2% acetic acid and acetonitrile. The limit of detection and limit of quantitation were 1 and 5 ng/g, respectively. Mean recoveries from various spiked tissues were 87.2% (ranging from 82.5 to 92.7%) for norfloxacin. The method has been successfully applied to determine norfloxacin in poultry muscle.

Platycodin D, a triterpenoid sapoinin from Platycodon grandiflorum, ameliorates cisplatin-induced nephrotoxicity in mice

Platycodin D (PD) is well known as a potent triterpenoid saponin having various pharmacological activities isolated from the root of Platycodon grandiflorum (Jacq.) A. DC. (Campanulaceae). We aimed to evaluate protective effect of PD on cisplatin (CDDP)-induced nephrotoxicity. Male ICR mice were allocated into five groups as follows: Negative control, CDDP alone and CDDP with PD (0.1, 1 and 5 mg/kg) treated group. PD was given for three consecutive days before CDDP injection. Increased blood urea nitrogen (BUN) and creatinine (CRE) levels in CDDP alone treated mice were decreased to normal range by pretreatment with PD. It also decreased nitric oxide (NO) and lipid peroxidation with increased antioxidant enzymes such as glutathione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD) in PD pretreated mice. In histopathological examination, pretreatment with PD showed ameliorated renal injury such as intraluminal cast formation and epithelial desquamation. Furthermore, over-expression of nuclear factor-kappa B p65 and apoptotic cells were suppressed by PD pretreatment. Taken together, PD pretreatment might be beneficial to CDDP-induced nephrotoxicity.

Embryo lethality and teratogenicity of a new fluoroquinolone antibacterial DW-116 in rats

Abstract DW-116, 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-l-piperazinyl)-1, 4-dihydro-4-oxoquinolone-3-carboxylic acid hydrochloride, is a newly developed fluoroquinolone antibacterial. The potential of DW-116 to induce developmental toxicity was investigated in Sprague-Dawley rats. DW-116 was administered by gavage to pregnant rats from days 6 to 16 of gestation at dose levels of 0, 31.3, 125, and 500 mg/kg per day. All dams were subjected to caesarean section on day 20 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. At 500 mg/kg, toxic effects including clinical signs of toxicity, suppressed body weight and decreased food intake were found in dams. An increase in the resorption rate, a decrease in the litter size, a reduction in the fetal weight, and a decrease in the placental weight were also seen. In addition, various types of external, visceral, and skeletal malformations occurred at an incidence of 17.9, 74.2 and 8.3%, respectively. Characteristic malformations included oedema, cleft palate, dilated cerebral ventricle, hypoplasia of lung and ventricular septum defect. A dramatic increase in the incidence of skeletal variations (55.6%) and retardations (94.4%) and a decrease in the number of ossification centres of sternebra, metacarpals, metatarsals and sacrocaudal vertebra were also observed. At 125 mg/kg, a reduction in the placental weight and an increase in the incidence of skeletal variations were found. There were no signs of maternal toxicity or embryotoxicity at 31.3 mg/kg. These results indicate that the fluoroquinolone antibacterial DW-116 is embryotoxic and teratogenic at minimally maternally toxic dose and is minimally embryotoxic at nonmaternally toxic dose in rats.

Single-Dose Oral Toxicity of Fermented Scutellariae Radix Extract in Rats and Dogs

The aim of this study was to investigate the acute oral toxicity of fermented Scutellariae Radix (JKTMHGu- 100) in rats and dogs. JKTM-HGu-100 was orally administered at a dose of 2,000 mg/kg in Sprague-Dawley rats. An escalating single-dose oral toxicity test in beagle dogs was performed at doses of 500, 1000, and 2000 mg/kg with 4-day intervals. Clinical signs, changes in body weight, mortality, and necropsy findings were examined for 2 weeks following oral administration. No toxicological changes related to the test substance nor mortality was observed after administration of a single oral dose of JKTM-HGu-100 in rats or dogs. Therefore, the approximate lethal dose (LD) for oral administration of JKTMHGu-100 in rats was considered to be over 2,000 mg/kg, and the maximum tolerance doses (MTDs) in rats and dogs were also estimated to be over 2,000 mg/kg. These results indicate that JKTM-HGu-100 shows no toxicity in rodents or non-rodents at doses of 2,000 mg/kg or less.

Protective Effects of Platycodon grandiflorum AqueousExtract on Thioacetamide-induced Fulminant HepaticFailure in Mice

The aim of the present study was to evaluate the protective activity of aqueous extract from Platycodon grandiflorum (BC703) on thioacetamide (TA)-induced hepatotoxicity in mice. We found that BC703 significantly decreased mortality and the change in serum transaminase following TA administration. The group treated with BC703 at doses of 1, 5, and 10 mg/kg produced significant hepatoprotective effects against TA-induced liver damage by decreasing the activities of serum enzymes, nitric oxide and lipid peroxidation in dose-dependent manners. Histopathological studies further substantiated the protective effect of BC703. These results show the hepatoprotective activity of aqueous extract from Platycodon grandiflorum on thioacetamide-induced fulminant hepatic failure.

Haematological Changes During Normal Pregnancy in New Zealand White Rabbits: A Longitudinal Study

Abstract: The present study was undertaken to investigate changes in haematology parameters over the course of normal pregnancy in New Zealand White rabbits. Blood samples were collected on gestational days (GD) 0, 4, 8, 12, 16, 20, 24, and 28. Red blood cell counts and haemoglobin concentrations on GD 20–28 were lower than those of normal non-pregnant rabbits. These values fluctuated slightly between GD 0 and 12 and subsequently decreased to reach a nadir on either GD 24 or 28. Haematocrit value in pregnant rabbits also decreased slightly in the third trimester, but the difference was not statistically noticeable. Mean corpuscular volume in pregnant rabbits increased gradually during the course of gestation and was larger on GD 24 than that in non-pregnant rabbits. There were no differences in mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration between pregnant and non-pregnant rabbits. Platelet counts on GD 24–28 were lower than that of normal non-pregnant rabbits. These values increased slightly in the first half of gestation and then decreased to reach a nadir on GD 28. Total white blood cell and lymphocyte counts on GD 24 were lower than those of normal non-pregnant rabbits. These values increased maximally by GD 4 and then decreased progressively to a minimum level on GD 24. No significant differences were observed in the numbers of neutrophils, eosinophils, basophils, and monocytes between pregnant and non-pregnant rabbits. Neutrophil counts of pregnant rabbits fluctuated minimally between GD 0 and 12 and then decreased to reach a lowest level on GD 24. Eosinophil counts increased to a maximum value on GD 4 and subsequently decreased to reach a nadir on GD 24. Basophil and monocyte counts were not different throughout the course of pregnancy. These data can be used not only as a historical database for the effective evaluation of data from reproductive toxicology studies, but also as a contribution to biological characterization of New Zealand White rabbits.

Platycodin D attenuates bile duct ligation-induced hepatic injury and fibrosis in mice.

Platycodin D (PD) is the major triterpene saponin in the root of Platycodon grandiflorum. The aim of the present study was to evaluate the protective effects of PD on bile duct ligation (BDL)-induced cholestasis in mice. Mice were allocated to five groups: sham, BDL alone, and BDL with PD treatment at 1, 2, and 4mg/kg. PD was administered to the mice for 28 consecutive days after the BDL operation. PD treatment of BDL-operated mice decreased serum alanine aminotransferase, serum aspartate aminotransferase, and total bilirubin levels by up to 37%, 31%, and 41%, respectively, in comparison with the levels in mice that underwent BDL alone. PD treatment attenuated oxidative stress, as evidenced by an increase in anti-oxidative enzyme levels glutathione and superoxide dismutase together with a decrease in lipid peroxidation and oxidative stress indices levels of malondialdehyde and nitric oxide. Histopathological studies further confirmed the protective effects of PD on cholestasis-induced hepatic injury and liver fibrosis in mice. In addition, nuclear factor-kappa B and inducible nitric oxide synthase levels significantly decreased after PD treatment, as did the levels of hepatocyte apoptosis. Taken together, these results suggest that PD treatment might be beneficial in cholestasis-induced hepatotoxicity.

Plasma disposition of toltrazuril and its metabolites, toltrazuril sulfoxide and toltrazuril sulfone, in rabbits after oral administration.

The objective of this study was to evaluate the pharmacokinetic profiles of toltrazuril (TZR), and its major metabolites toltrazuril sulfoxide (TZR x SO) and toltrazuril sulfone (TZR x SO(2)) in rabbits after oral administrations. Rabbits were dosed once with 10 and 20mg/kg TZR via stomach tube with manual restraint. The plasma concentrations of TZR, TZR x SO and TZR x SO(2) were determined by liquid chromatography/mass spectrometry. Plasma concentration-time data after single oral administration were analyzed by a non-compartmental analysis. Plasma peak concentrations of TZR, TZR x SO and TZR x SO(2) were 30.2+/-1.5microg/mL at 20.0+/-6.9h, 8.9+/-1.3microg/mL at 20.0+/-6.9h and 14.7+/-3.9microg/mL at 96.0+/-0.0h after oral administration of TZR with 10mg/kg bw, respectively. The terminal elimination half-lives for TZR, TZR x SO and TZR x SO(2) after oral dose of 10mg/kg were 52.7+/-3.6, 56.1+/-10.7 and 76.7+/-7.5h, respectively. Plasma peak concentrations of TZR, TZR x SO and TZR x SO(2) were 39.4+/-1.2microg/mL at 28.0+/-6.9h, 12.5+/-3.9microg/mL at 20.0+/-6.9h and 24.9+/-8.74microg/mL at 112.0+/-6.9h after oral administration of TZR with 20mg/kg bw, respectively. The terminal elimination half-lives for TZR, TZR x SO and TZR x SO(2) after oral dose of 20mg/kg were 56.7+/-1.9, 68.8+/-12.5 and 82.3+/-12.6h, respectively. In conclusion, TZR was very well-absorbed through the gastrointestinal tract and rapidly metabolized to TZR x SO and TZR x SO(2) in rabbits after oral administration. TZR x SO(2) was actually more slowly eliminated than TZR and TZR x SO.