• Proceedings of the Korean Society of Toxicology Conference
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• 2003.10b
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• pp.155-156
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• 2003

RNA was isolated from mucosal tissue of the duodenum, jejunum, ileum and colon after perfusion. The gene expression profiles were measured using Affymetrix GeneChip(R) analysis. Prodrug valacyclovir permeability was 5-fold and 2-fold higher than the parent drug acyclovir in the jejunum and ileum, respectively.(omitted)

• Proceedings of the Korean Society of Toxicology Conference
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• 2003.10b
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• pp.158-159
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• 2003

We have cloned and functionally expressed a sodium dependent human nucleoside transporter, hCNT2, from a CNS cancer cell line U251. Our cDNA clone of hCNT2 had the same predicted amino acid sequence as the previously cloned hCNT2 transporter. Of the several cell lines studied, the best hCNT2 transport function was obtained when transiently expressed in U251 cells.(omitted)

• Toxicological Research
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• v.29 no.1
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• pp.27-34
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• 2013

This study was conducted to investigate the potential embryo-fetal toxicity and toxicokinetics of the antimalarial agent artesunate (ARTS) in Sprague-Dawley rats. Pregnant rats were administered ARTS daily from gestational day 6~15 via oral gavage, at test doses of 0, 2, 4, or 8 mg/kg (22 females per group). The fetuses were examined for external, visceral, and skeletal abnormalities on gestational day 20. With regard to the dams, there were no deaths, treatment-related clinical signs, changes in body weight, or food intake in any of the treatment groups. There were no treatment-related gross findings at necropsy in any treatment group. In the 8 mg/kg group, there was a decrease in gravid uterine weight and in the weight of female fetuses. There was also an increase in fetal deaths (primarily late resorptions) and an increase in post-implantation losses (37%) at 8 mg/kg. An increase in the incidence of visceral and skeletal variations at 4 and 8 mg/kg was observed. These defects included minor changes in the appearance of the kidney and thymus, as well as absent ribs or thoracic vertebrae. Toxicokinetics were assessed in a parallel study, using 4 mated females per group. Using liquid chromatography-mass spectrometry (LC-MS) analysis, the concentration of ARTS and its metabolite dihydroartemisinin (DHA) were quantified in plasma from rats on gestational days 5, 6, 10, and 15. Amniotic fluid was assayed for ARTS and DHA on gestational day 15. There was evidence of rapid conversion of ARTS to the metabolite DHA in maternal plasma, since ARTS could not be consistently detected in plasma at the three doses tested. ARTS and DHA were not detected in amniotic fluid at gestational day 15, indicating limited placental transfer of the two agents. The embryo-fetal no-observable-adverse-effect level (NOAEL) of the test item was considered to be 8 mg/kg/day for dams, and 2 mg/kg/day for embryo-fetal development.

• Toxicological Research
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• v.29 no.1
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• pp.53-60
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• 2013

Studies on milk transfer of drugs in non-human primates (NHPs) are among the crucial components in the assessment of peri- and postnatal toxicity because of the similarity between NHPs and humans. To evaluate the milk transfer of valproic acid (VPA) in NHPs, the toxicokinetics of VPA, an antiepileptic drug, were studied in pregnant cynomolgus monkeys. VPA was administered once daily to pregnant cynomolgus monkeys at doses of 0, 30, 90, and 270 mg/kg by oral gavage from Day 100 of gestation (GD 100) to Day 31 of lactation (LD 31). Concentrations of VPA and its metabolite, 4-ene-VPA, in the maternal plasma on GD 100, GD 140, and LD 30, and concentrations of VPA and 4-ene-VPA in the offspring plasma and milk on LDs 30 and 31, respectively, were quantified using liquid chromatography tandem mass spectrometry (LC/MS/MS). After administration of a single oral dose of VPA to pregnant monkeys on GD 100, the concentrations of VPA and 4-ene-VPA were generally quantifiable in the plasma of all treatment groups up to 24 hr after administration, which showed that VPA was absorbed and that the monkeys were systemically exposed to VPA and 4-ene-VPA. After administration of multiple doses of VPA to the monkeys, VPA was detected in the pup's plasma and in milk taken on LD 30 and LD 31, respectively, which showed that VPA was transferred via milk, and the pup was exposed to VPA. Further, the concentration of VPA in the milk increased with an increase in the dose. Extremely low concentrations of 4-ene VPA were detected in the milk and in the pup plasma. In conclusion, pregnant monkeys were exposed to VPA and 4-ene-VPA after oral administration of VPA at doses of 30, 90, and 270 mg/kg/day from GD 100 to LD 31. VPA was transferred via milk, and the VPA exposure to the pup increased with an increase in the dose of VPA. The metabolite, 4-ene VPA, was present in extremely low concentrations (< 0.5 ${\mu}g/ml$) in the milk and in the pup plasma. In this study, we established methods to confirm milk transfer in NHPs, such as mating and diagnosis of pregnancy by examining gestational sac with ultrasonography, collection of milk and pup plasma and determination of toxicokinetics, using cynomolgus monkeys.

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2004.05a
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• pp.79-79
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• 2004

• Korean Journal of Clinical Pharmacy
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• v.15 no.1
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• pp.61-67
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• 2005

This study was designed to establish a strategy for the bioequivalence study of doxifluridine, an anticancer drug, in dogs instead of cancer patients. Although the results from animals may not occur in the same manner from human, those would be worth enough in terns of the bioequivalence. As for critically ill population such as cancer patients, bioequivalence studies in animals bring many advantages. Six healthy Beagle dogs were selected on the basis of hematology and blood chemistry test. After an over night fast, 200 mg of doxifluridine was orally administered, and blood was serially taken up to 12 hours. Plasma concentration of doxifluridine was measured using a newly validated bioanalytical method by a HPLC coupled tandem mass spectrometry. Time course of plasma doxifluridine concentration was analyzed with non-compartmental and compartmental approaches. Consequently, we represented hematology and blood chemistry database for the selection of healthy Beagle dogs, and suggested a sensitive and validated analytical method of doxifluridine, as well as a study design for the bioequivalence of doxifluridine in dogs.

• Toxicological Research
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• v.13 no.3
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• pp.237-245
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• 1997

As the development of a pharmaceutical product is a dynamic process which involves continuousfeed-back between non-clinical and clinical studies, the integration of pharmacokinetics into toxicity testing became increasingly important in recent years. Toxicokinetic measurements in the toxicity studies is considered to be an important scientific approach in the interpretation of the toxicology findings and the promotion of rational study design development. Primarily this research project was conducted to determine the systemic exposure achieved in acute toxicity test and its relationship to dose level and the time course of the toxicity study. Acute hepatotoxicity study and its relevant toxicokinetic study in mice were performed using acetarninophen (AA) as a model compound. The correlation between acute hepatotoxicity indices and toxicokinetic parameters following intraperitoneally administration of various dosages of AA in mice was evaluated and discussed minutely in the text. Based on these studies, single-dose toxicity testing of AA including kinetic studies was evaluated in ICR mice for 7 days and interpreted in the text. Our results from the integration of toxicokinetic monitoring into single-dose toxicity study enable to elucidate the relation of the exposure achieved in toxicity study to toxicological findings and assist in the selection of appropriate dose levels for use in repeated-dose toxicity or later studies.

• Toxicological Research
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• v.30 no.3
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• pp.179-184
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• 2014

Xenobiotics causing a variety of toxicity in biological systems could be classified as two types, inorganic and organic chemicals. It is estimated that the organic xenobiotics are responsible for approximately 80~90% of chemical-induced toxicity in human population. In the class for toxicology, we have encountered some difficulties in explaining the mechanisms of toxicity caused especially by organic chemicals. Here, a simple flowchart was introduced for explaining the mechanism of toxicity caused by organic xenobiotics, as the central dogma of molecular biology. This flowchart, referred to as a central dogma, was described based on a view of various aspects as follows: direct-acting chemicals vs. indirect-acting chemicals, cytochrome P450-dependent vs. cytochrome P450-independent biotransformation, reactive intermediates, reactivation, toxicokinetics vs. toxicodynamics, and reversibility vs. irreversibility. Thus, the primary objective of this flowchart is to help better understanding of the organic xenobiotics-induced toxic mechanisms, providing a major pathway for toxicity occurring in biological systems.

• Korean Journal of Veterinary Research
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• v.40 no.3
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• pp.471-478
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• 2000

The pharmacokinetic properties of KR-V compounds, recently developed as new anti-HIV agents, were studied after i.v. and p.o. administration in rats. The concentrations of the KR-V series were determined in rat plasma using an high-performance liquid chromatography (HPLC)-UV detection system. Of the 19 KR-V compounds investigated in the present study, only KR-V 3, 10, 14, 16 and 18-1 showed oral bioavailability. The plasma concentration-time data could be adequately described by an one-compartment open model. In the i.v. kinetic study (10mg/kg), the CLt of KR-V 3, 10, 14 and 16 (>4L/hr/kg) were significantly higher than that of KR-V 18-1 (1.1 L/hr/kg). The AUC of KR-V 18-1 was greater ($8.97{\mu}g{\cdot}hr/ml$) than that of the other compounds, but the Vd (0.58 L/kg) was lower. In the p.o. kinetic study (50mg/kg), although the t-1/2 of KR-V 18-1 was shorter than that of the other compounds, the AUC ($3.659{\mu}g{\cdot}hr/ml)$ and $C_{max}(1.891{\mu}g/ml$) were markedly higher. In a seperated in vitro experiment, only KR-V 18-1, of the 5 compounds with bioavailibility, exhibits potent activity against HIV-1 mutant strains. Therefore, KR-V 18-1 is expected to become a new potent anti-AIDS drug candidate/lead compound.

• Korean Journal of Veterinary Research
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• v.35 no.4
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• pp.815-822
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• 1995

The toxicokinetics of rifapentine was studied after an oral administration to beagle dogs. High-performance liquid chromatography(HPLC) using column-switching technique was performed to determine the serum concentrations of rifapentine. The pharmacokinetic profiles of rifapentine were analysed using one-compartment open model. Following a single oral administration of 10mg/kg, pharmacokinetic parameters were determined as follows: maximum serum concentration($C_{max}$), $28.90{\mu}g/ml$; maximum concentration time($T_{max}$), 3.7hr; elimination half-life($t_{1/2}$, 4.7hr; area under the curve(AUC), $339.0{\mu}g{\cdot}hr/ml$; volume of disiribution/bioavailability (Vd/F), 0.21 l/kg; lag time, 24min; absorption rate constant($k_a$), $0.445hr^{-1}$; elimination rate constant($k_{el}$), $0.148hr^{-1}$. After 6 month multiple oral doses of 10mg/kg/day, parameters were as follows: $C_{max}$, $34.40{\mu}g/ml$; $T_{max}$, 2.6hr; $t_{1/2}$, 6.7hr; AUC, $391.3{\mu}g{\cdot}hr/ml$; Vd/F, 0.291/kg; $k_a$, $0.976hr^{-1}$; $k_{el}$, $0.104hr^{-1}$. The consistant kinetic parameters after a single and multiple oral administration show that there was no accumulation of rifapentine after 6 month oral administration. We also simulated the concentration of rifapentine after oral multiple administration of 10 and 50mg/kg/ day, based on the parameters obtained form the single administration. The measured serum concentrations of rifapentine were well fitted to the simulated results. The simulated results show that rifapentine readily reaches to steady-state after about 3 doses and the steady-state serum concentrations($C_{ss}$) are fluctuated in between $2.2{\sim}25.2{\mu}g/ml$, and $10.6{\sim}125.2{\mu}g/ml$ at the doses of 10 and 50mg/kg/day, respectively.