• Archives of Pharmacal Research
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• v.17 no.2
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• pp.124-130
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• 1994

Plasma phamacokinetics and renal excretion of theophylline (TP) and its metabolities were ivnestigated in rats. Plasma concentrations of TP declined in a monoexponential manner, while those of 1-methyluric (MU) and 1,3-dimethyluric(DMU) declined in a biexponential manner upon respective iv bolus injection of each compound at 6mg/kg dose. The total body clearances $(CL_r)$ of the metabolites were 4-6 fold larger than that of TP, while the distribution volumes of them at steady-state $(Vd_{ss})$ were 40-50% smaller than that of TP. The metabolites showed their plasma peaks in 30 min after iv injection of TP indicating than that to MU. Renal excretion of TP and its metabolites was studied in urine flow rate (UFR)-controlled rats. The renal clearance $(CL_r)$ of TP was inversely related to pasma TP concentrations, and much smaller than the glomerular filtration rate (GFR) suggesting tubular secretion and profound reabsorption in the renal tubule. The $(CL_r)$ of each metabolite also showed that inverse relationship, but far exceeded GFR suggesting that tubular secretion than GFR by ip injection of probenecid (142.7 mg/kg). It supports that the metabolies are secreted in the renal tubule, and suggests that they share a common transport system in their sectrtion processes with probenecid. On the other hand, the $(CL_r)$ of TP was not affected significantly by the probenecid treatment. Considering the inverse relationship of TP between the $(CL_r)$ and its ploasma concentrations,no effect of probenecid on $(CL_r)$ of TP is most likely due to negligible contribution of the secretion to the overall $(CL_r)$ of TP.

• Preventive Nutrition and Food Science
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• v.19 no.4
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• pp.321-326
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• 2014

In this study, we developed a method to quantify esculetin (6,7-dihydroxycoumarin) in plasma and tissues using HPLC coupled with ultraviolet detection and measured the level of esculetin in rat plasma after oral administration. The calibration curve for esculetin was linear in the range of 4.8 ng/mL to 476.2 ng/mL, with a correlation coefficient ($r^2$) of 0.996, a limit of detection value of 33.2 ng/mL, and a limit of quantification value of 100.6 ng/mL. Recovery rates for the 95.2 ng/mL and 190.5 ng/mL samples were 95.2% and 100.3%, within-runs and 104.8% and 101.0% between-runs, respectively. The relative standard deviation was less than 7% for both runs. In the pharmacokinetic analysis, the peak plasma esculetin level was reached 5 min after administration ($C_{max}=173.3ng/mL$; $T_{1/2}=45min$; $AUC_{0{\sim}180min}=5,167.5ng{\cdot}min/mL$). At 180 min post-administration (i.e., after euthanasia), esculetin was only detectable in the liver ($30.87{\pm}11.33ng/g$) and the kidney ($20.29{\pm}7.02ng/g$).

• Journal of fish pathology
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• v.21 no.2
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• pp.107-117
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• 2008

The pharmacokinetic properties of oxytetracycline (OTC) were studied after dipping and oral administration to cultured olive flounder, Paralichthys olivaceus (600 g). Plasma concentrations of OTC were determined after oral dosage (50, 100 and 200 mg/kg body weight) and dipping (50, 100 and 200 ppm, 1 h) in olive flounder (average 600 g, 23±1℃). Plasma samples were taken at 3, 5, 10, 15, 24, 32, 48, 72, 120, 168 and 240 h post-dose. In oral dosage of 50, 100 and 200 mg/kg, the peak plasma concentrations of OTC, which attained at 3 h post-dose, were 0.34, 0.44 and 1.18 ㎍/㎖, respectively. In dipping of 50, 100 and 200 ppm, those of OTC which also observed at 5 h post-dose, were 0.43, 0.38 and 0.64 ㎍/㎖, respectively. Plasma concentrations of OTC were not measurable at 240 h post-dose in all experiments. The kinetic profile of absorption, distribution and elimination of OTC in plasma were analyzed fitting to a one-compartment model by WinNonlin program. The following parameters were calculated for a single dosage of 50, 100 and 200 mg/kg body weight, respectively: AUC (the area under the concentration-time curve)=31.40, 28.07 and 32.97 ㎍∙h/㎖; T1/2 (half-life)􀆫0.89, 1.12 and 0.43 h; Tmax (time for maximum concentration)= 5.25, 3.70 and 7.30 h, Cmax (maximum concentration)=0.25, 0.38 and 0.61 ㎕/㎖. Following dipping at 50, 100 and 200 ppm, these parameters were AUC􀆫15.51, 14.63 and 19.72 ㎍∙h/㎖; T1/2= 0.75, 0.41 and 0.74 h; Tmax=4.90, 7.08 and 4.68 h, Cmax=0.40, 0.32 and 0.46 ㎕/㎖.

• Mass Spectrometry Letters
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• v.12 no.4
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• pp.200-205
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• 2021

Polynemoraline C, a pyridocoumarin alkaloid, exhibits anticholinergic, anti-inflammatory, antitumor, and antimicrobial activities. A sensitive analytical method of polynemoraline C in mouse plasma was developed and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Polynemoraline C and ¹³C-caffeine (internal standard) in mouse plasma were extracted using a liquid-liquid extraction method coupled with ethyl acetate. This extraction method resulted in high and reproducible extraction recovery in the range of 73.49%-77.31% with no interfering peaks around the peak retention time of polynemoraline C and ¹³C-caffeine. The standard calibration curves for polynemoraline C were linear over the range of 0.5-200 ng/mL with r² > 0.985. The accuracy, precision, and the stability of the data were within acceptable limits on the FDA guideline. After intravenous and oral administration of polynemoraline C at doses of 5 and 30 mg/kg, respectively, the present method was successfully applied to the pharmacokinetic study of polynemoraline C. Polynemoraline C in mouse plasma showed a multi-exponential elimination pattern with a high volume of distribution values. This compound's absolute oral bioavailability was found to be 17.0%. Polynemoraline C's newly developed LC-MS/MS method can be used for further studies on the efficacy, toxicity, and biopharmaceutics of polynemoraline C, as well as its pharmacokinetic studies.

• Korean Journal of Veterinary Research
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• v.58 no.4
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• pp.183-192
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• 2018

Although hyaluronic acid (HA) has been developed as a nanoparticle (NP; 320-400 nm) for a drug delivery system, the tissue targeting efficacy and the pharmacokinetics of HA-NPs are not yet fully understood. After a dose of 5 mg/kg of cyanine 5.5-labeled HA-NPs or HA-polymers was intravenously administrated into mice, the fluorescence was measured from 0.5 h to 28 days. The HA-NPs fluorescence was generally stronger than that of HA-polymers, which was maintained at a high level over 7 days in vivo, after which it gradually decreased. Upon ex vivo imaging, liver, spleen, kidney, lung, testis and sublingual gland fluorescences were much higher than that of other organs. The fluorescence of HA-NPs in the liver, spleen and kidney was highest at 30 min, where it was generally maintained until 4 h, while it drastically decreased at 1 day. However, the fluorescence in the liver and spleen increased sharply at 7 days relative to 3 days, then decreased drastically at 14 days. Conversely, the fluorescence of HA-polymers in the lymph node was higher than that of HA-NPs. The results presented herein may have important clinical implications regarding the safety of as self-assembled HA-NPs, which can be widely used in biomedical applications.

• Journal of fish pathology
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• v.24 no.1
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• pp.29-37
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• 2011

Effects of temperature ($13{\pm}1.5^{\circ}C$, $23{\pm}1.5^{\circ}C$) on the pharmacokinetic properties of nalidixic acid (NA) and piromidic acid (PA) were studied after oral administration to cultured black rockfish, Sebastes schlegeli. Serum concentrations of NA and PA were determined using HPLC-UV detector after a single dosage of 60 mg/kg body weight. At $23{\pm}1.5^{\circ}C$, the peak serum concentrations of NA and PA, which attained at 24 h post-dose, were 5.87 and $0.43\;{\mu}g/ml$, respectively. At $13{\pm}1.5^{\circ}C$, the peak serum concentrations of NA and PA, which attained at 10 h post-dose, were 6.22 and $1.57\;{\mu}g/ml$, respectively. Better absorption of PA was noted at $13{\pm}1.5^{\circ}C$ compared to $23{\pm}1.5^{\circ}C$. However, absorption of NA was not affected significantly by temperature. The elimination of NA and PA from serum of black rockfish was considerably faster at $23{\pm}1.5^{\circ}C$ than at $13{\pm}1.5^{\circ}C$. The kinetic profile of absorption, distribution and elimination of NA and PA in serum were analyzed by fitting to a one compartment model, with WinNonlin program. The AUC, $T_{1/2}$, $T_{max}$ and $C_{max}$, respectively, were: $161.25\;{\mu}g{\cdot}h/ml$, 0.15 h, 12.29 h and $8.91\;{\mu}g/ml$ at $23{\pm}1.5^{\circ}C$, and $134.12{\mu}g{\cdot}h/ml$, 0.18 h, 8.79 h and $5.00\;{\mu}g/ml$ at $13{\pm}1.5^{\circ}C$ with NA; $41.57\;{\mu}g{\cdot}h/ml$, 0.58 h, 8.24 h and $0.21\;{\mu}g/ml$ at $23{\pm}1.5^{\circ}C$, and $40.36\;{\mu}g{\cdot}h/ml$, 0.59 h, 5.04 h and $1.20\;{\mu}g/ml$ at $13{\pm}1.5^{\circ}C$ with PA.

• Journal of fish pathology
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• v.22 no.2
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• pp.125-135
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• 2009

The pharmacokinetic properties of oxolinic acid (OA) were studied after oral administration, intraperitoneal injection and dipping to cultured olive flounder, Paralichthys olivaceus (average 90 g, $23{\pm}1{^{\circ}C}$). Plasma samples were taken at 3, 5, 10, 15, 24, 30, 48, 96 and 144 h post-dose. In oral dosage at 15, 30 and 60 ㎎/㎏, the peak plasma concentrations of OA, which attained at 10~15 h post-dose, were 1.92, 2.45 and 3.72 $\mu{g}/m\ell$, respectively. In intraperitoneal injection with 10 and 20 ㎎/㎏, the peak plasma concentrations of OA, which attained at 10 h post-dose, were 4.1 and 4.8 $\mu{g}/m\ell$, respectively. In dipping in 30 and 50 ppm for 1 h, peak concentrations were observed at 5 h and 30 h post-dose, were 0.22 and 0.38 $\mu{g}/m\ell$, respectively. The kinetic profile of absorption, distribution and elimination of OA in plasma were analyzed fitting to a one-compartment model by WinNonlin program. Calculated parameters for a single oral dosage of 15, 30 and 60 ㎎/㎏, respectively, were: AUC (the area under the concentration-time curve)=70.93, 120.0 and 141.86 $\mu{g}$ $h/m\ell$ $T_{max}$ (time for maximum concentration)=16.22, 20.39 and 17.33 h; $C_{max}$ (maximum concentration)=���D1.61, 2.40 and 3.01 $\mu{g}/m\ell$. Following intraperitoneal injection of 10 and 20 ㎎/㎏, these parameters were AUC=184.7 and 315.92 $\mu{g}$ $h/m\ell$ $T_{max}$=5.91 and 6.26 h; $C_{max}$=4.19 and 4.45 $\mu{g}/m\ell$. Following dipping at 30 and 50 ppm, these parameters were AUC=17.58 and 21.69 $\mu{g}$ $h/m\ell$ $T_{max}$=19.08 and 31.43 h; $C_{max}$x=0.22 and 0.25 $\mu{g}/m\ell$.

• Journal of fish pathology
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• v.23 no.3
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• pp.357-367
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• 2010

The pharmacokinetic properties of amoxicillin trihydrate (Amox) were studied after single oral administration and single intravenous injection to cultured eel, Anguilla japonica, respectively (average $220{\pm}10\;g$, $28{\pm}1^{\circ}C$). Plasma samples were taken at 3, 5, 10, 15, 24, 30, 48, 96 and 144 h post-dose. The kinetic profile of absorption, distribution and elimination of Amox in plasma were analyzed fitting to a two-compartment model by WinNonlin program. In oral dosage of 40 and 80 mg/kg body weight, the peak plasma concentrations of Amox, which attained at 3~12 h post-dose, were 3.4 and $3.3\;{\mu}g/ml$, respectively. In intravenous injection with 1 mg/kg, the peak plasma concentrations of Amox, which attained at 9 h post-dose, was $7.2\;{\mu}g/ml$. The following parmeters were calculated for a single oral dosage of 40 and 80 mg/kg body weight, respectively: AUC (the area under the concentration-time curve)= 464 and $667\;{\mu}g{\cdot}h/ml$; $T_{max}$ (time for maximum concentration)= 2.1 and 3.6 h; $C_{max}$ (maximum concentration)= 3.04 and $3.4\;{\mu}g/ml$. Following intravenous injection at 1 mg/kg, this parameters were AUC= $748\;{\mu}g{\cdot}h/ml$; $C_{max}=4.2\;{\mu}g/ml$. The apparent oral bioavailability at 40 and 80 mg/kg were 1.6 and 1.1%, respectively. Despite using the trihydrate form of amoxicillin, the oral bioavailability was low in eel.

• Journal of Life Science
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• v.29 no.6
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• pp.653-661
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• 2019

The first small interfering RNA (siRNA) therapeutics have recently been approved by the Food and Drug Administration in the U.S., and the demand for a new RNA therapeutics bioanalysis method-which is essential for pharmacokinetics, including the absorption, distribution, metabolism, and excretion of siRNA therapeutics-is rapidly increasing. The stem-loop real-time qPCR (RT-qPCR) assay is a useful molecular technique for the identification and quantification of small RNA (e.g., micro RNA and siRNA) and can be applied for the bioanalysis of siRNA therapeutics. When the anti-HPV E6/E7 siRNA therapeutic was used in preclinical trials, the established stem-loop RT-qPCR assay was validated. The limit of detection was sensitive up to 10 fM and the lower limit of quantification up to 100 fM. In fact, the reliability of the established test method was further validated in three intra assays. Here, the correlation coefficient of $R^2$>0.99, the slope of -3.10 ~ -3.40, and the recovery rate within ${\pm}20%$ of the siRNA standard curve confirm its excellent robustness. Finally, the circulation profiles of siRNAs were demonstrated in rat serum, and the pharmacokinetic properties of the anti-HPV E6/E7 siRNA therapeutic were characterized using a stem-loop RT-qPCR assay. Therefore, the stemloop RT-qPCR assay enables accurate, precise, and sensitive siRNA duplex quantification and is suitable for the quantification of small RNA therapeutics using small volumes of biological samples.

• Toxicological Research
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• v.6 no.2
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• pp.205-213
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• 1990

The regulation of neurotoxicants has usually been based upon setting reference doses by dividing a no observed adverse effect level (NOAEL) by uncertainty factors that theoretically account for interspecies and intraspecies extraploation of experimental results in animals to humans. Recently, we have proposed a four-step alternative procedure which provides quantitative estimates of risk as a function of dose. The first step is to establish a mathematical relationship between a biological effect or biomarker and the dose of chemical administered. The second step is to determine the distribution (variability) of individual measurements of biological effects or their biomarkers about the dose response curve. The third step is to define an adverse or abnormal level of a biological effect or biomarker in an untreated population. The fourth and final step is to combine the information from the first three steps to estimate the risk (proportion of individuals exceeding on adverse or abnormal level of a biological effect or biomarker) as a function of dose. The primary purpose of this report is to enhance the certainty of the first step of this procedure by improving our understanding of the relationship between a biomarker and dose of administered chemical. Several factors which need to be considered include: 1) the pharmacokinetics of the parent chemical, 2) the target tissue concentrations of the parent chemical or its bioactivated proximate toxicant, 3) the uptake kinetics of the parent chemical or metabolite into the target cell(s) and/or membrane interactions, and 4) the interaction of the chemical or metabolite with presumed receptor site(s). Because these theoretical factors each contain a saturable step due to definitive amounts of required enzyme, reuptake or receptor site(s), a nonlinear, saturable dose-response curve would be predicted. In order to exemplify this process, effects of the neurotoxicant, methlenedioxymethamphetamine (MDMA), were reviewed and analyzed. Our results and those of others indicate that: 1) peak concentrations of MDMA and metabolites are ochieved in rat brain by 30 min and are negligible by 24 hr, 2) a metabolite of MDMA is probably responsible for its neurotoxic effects, and 3) pretreatment with monoamine uptake blockers prevents MDMA neurotoxicity. When data generated from rats administerde MDMA were plotted as bilolgical effect (decreases in hippocampal serotonin concentrations) versus dose, a saturation curve best described the observed relationship. These results support the hypothesis that at least one saturable step is involved in MDMA neurotoxicity. We conclude that the mathematical relationship between biological effect and dose of MDMA, the first step of our quantitative neurotoxicity risk assessment procedure, should reflect this biological model information generated from the whole of the dose-response curve.