• Journal of Pharmaceutical Investigation
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• 제31권4호
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• pp.209-216
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• 2001

The purpose of the present study was to investigate the hepatic uptake and biliary excretion of l-anilino-8-naphthalene sulfonate (ANS) in vivo. The plasma concentration and liver concentration of ANS were determined after its i.v. bolus administration at a dose of $30\;{\mu}mol/kg$ in rats. The hepatic uptake clearance $(CL_{uptake})$ of ANS was 0.1 ml/min/g liver. On the basis of the unbound concentration of ANS, the permeability-surface area product $(PS_{influx})$ was calculated to be l0.4 ml/min/g liver, being comparable of in vitro data. On the other hand, we determined the plasma concentration, liver concentration and biliary excretion rate of ANS at steady-state after its i. v. infusion $(0.2-1.6\;{\mu}mol/min/kg)$ in rats. The excretion clearance $(CL_{excretion})$ of ANS showed Michaelis-Menten kinetics with increasing the infusion rate. The permeability-surface area product $(PS_{excretion})$ based on the unbound concentration in the liver was calculated to be 0.0165 ml/min/g liver, which is negligible compared with the intrinsic clearance $(CL_{int}=3.3\;ml/min/g\;liver)$ by rat liver microsomes. The sequestration process of ANS, therefore, was considered to be mainly due to the metabolic process in the liver $(PS_{seq}{\risingdotseq}CL_{int})$. Furthermore, $PS_{efflux}$ value calculated from $PS_{influx}$ and $PS_{seq}$ was 4.4 ml/min/g liver, which was comparable of in vitro data. In conclusion, in vivo parameters such as $PS_{influx}$, $PS_{efflux}$ and $PS_{seq}$ in the present study showed good in vivo-in vitro relationship. Thus, the kinetic analysis method proposed in the present study would be useful to analyze the hepatic transport of drugs in vivo.

• Journal of Pharmaceutical Investigation
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• 제30권4호
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• pp.273-278
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• 2000

Several topical preparations containing lidocaine, a widely used local anesthetic agent, have been developed and marketed recently for the treatment of premature ejaculation. In this study, microemulsion(ME)-based hydrogels containing lidocaine were prepared by dispersing ME to hydrogel bases such as Carbopol, sod. alginate, and sod. carboxymethylcellulose. Lidocaine-containing ME was thermodynamically stable over 6 months and had a diameter ranging from 10 to 100 nm. In vitro skin penetration of lidocaine from ME-based hydrogels followed apparent zero-order kinetics. ME-based hydrogel showed higher drug penetration during fifteen minutes after application than alcoholic hydrogel, reference preparation. Tail flick test in rat was introduced to compare in vivo local anesthetic effects of different hydrogels, and the results showed that ME-based hydrogels are superior to other hydrogels. In optical microscopy, recrystallization of lidocaine was observed within 5 min after application of reference hydrogel, but there was no change in ME-based hydrogels even after 30 minnute. These results indicated that ME-based hydrogels had some advantages in skin penetration, anesthetic effect and physical stability compared with alcoholic hydrogels. Finally it is possible to conclude that ME-based hydrogels containing lidocaine is a good topical drug delivery system for the treatment of premature ejaculation.

• IMMUNE NETWORK
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• 제12권1호
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• pp.18-26
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• 2012

Background: Vitamin C is an essential nutrient for maintaining human life. Vitamin C insufficiency in the plasma is closely related with the development of scurvy. However, in vivo kinetics of vitamin C regarding its storage and consumption is still largely unknown. Methods: We used $Gulo^{-/-}$ mice, which cannot synthesize vitamin C like human. Vitamin C level in plasma and organs from $Gulo^{-/-}$ mice was examined, and it compared with the level of wild-type mice during 5 weeks. Results: The significant weight loss of $Gulo^{-/-}$ mice was shown at 3 weeks after vitamin C withdrawal. However, there was no differences between wild-type and vitamin C-supplemented $Gulo^{-/-}$ mice (3.3 g/L in drinking water). The concentration of vitamin C in plasma and organs was significantly decreased at 1 week after vitamin C withdrawal. Vitamin C is preferentially deposited in adrenal gland, lymph node, lung, and brain. There were no significant changes in the numbers and CD4/CD8 ratio of splenocytes in $Gulo^{-/-}$ mice with vitamin C withdrawal for 4 weeks. And the architecture of spleen in $Gulo^{-/-}$ mice was disrupted at 5 weeks after vitamin C withdrawal. Conclusion: The vitamin C level of $Gulo^{-/-}$ mice was considerably decreased from 1 week after vitamin C withdrawal. Vitamin C is preferentially stored in some organs such as brain, adrenal gland and lung.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 제4회 추계심포지움
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• pp.99-113
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• 1996

Taurine, a ${\beta}$-amino acid, plays an important role as a neuromodulator and is necessary for the normal development of the brain. Since de novo synthesis of taurine in the brain is minimal and in vivo studies suggest that taurine does not cross the blood-brain barrier, the blood-cerebrospinal fluid (CSF) barrier is likely to play a role in taurine transport between the central nervous system and the systemic circulation. Therefore, we examined in vivo elimination of taurine from the CSF in the rat to characterize in vivo kinetics of elimination for taurine from the CSF is consistent with the in vitro study. Using a stereotaxic device, cannulaes were placed into the lateral ventricle and the cisterna magna of the rat. Radio-labelled taurine and inulin (a marker of CSF flow) were injected into the lateral ventricle, and the concentrations of the labelled compounds in the CSF were monitored for up to 3 hrs in the cisterna magna. The apparent clearance of taurine from CSF was greater than the estimated CSF flow (p<0.005), indicating that there is a clearance process in addition to the CSF flow. Taurine distribution into the choroid plexus was at least 10 fold higher than that found in other brain areas (e.g., cerebellum, olfactory bulb and cortex). When unlabelled taurine was co-administered with radio-labelled taurine, the apparent clearance of the labeled taurine was reduced (p<0.01), suggesting a saturable disposition of taurine from CSF. Distribution of taurine into the choroid plexus, cerebellum, olfactory bulb and cortex was similarly diminished, indicating that the saturable uptake of taurine into these tissues is responsible for the non-linear disposition. A pharmacokinetic model involving first order elimination and saturable distribution described these data adequately. The Michaelis-Menten rate constant estimated from in vivo elimination study is similar to that obtained in the in vitro uptake experiment Collectively, our results demonstrate that taurine is transported in the choroid plexus via a taurine is cleared from the CSF via a saturable process. This process may be functionally relevant to taurine homeostasis in the brain.

• Nuclear Medicine and Molecular Imaging
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• 제41권2호
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• pp.118-131
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• 2007

Neurotransmitter imaging with radiopharmaceuticals plays major role for understanding of neurological and psychiatric disorders such as Parkinson's disease and depression. Radiopharmaceuticals for neurotransmitter imaging can be divided to dopamine transporter imaging radiopharmaceuticals and serotonin trnasporter imaging radiopharmaceuticals. Many kinds of new dopamine transporter imaging radiopharmcaeuticals has a tropane ring and they showed different biological properties according to the substituted functional group on tropane ring. After the first clinical trials with $[^{123}I]{\beta}-CIT$, alkyl chain substituent introduced to tropane ring amine to decrease time for imaging acquisition and to increase selectivity. From these results, $[^{123}I]PE2I$, [18F]FE-CNT, $[^{123}I]FP-CIT$ and $[^{18}F]FP-CIT$ were developed and they showed high uptake on the dopamine transporter rich regions and fast peak uptake equilibrium time within 4 hours after injection. $[^{11}C]McN$ 5652 was developed for serotonin trnasporter imaging but this compound showed slow kinetics and high background radioactivity. To overcome these problems, new diarylsulfide backbone derivatives such as ADAM, ODAM, AFM, and DASB were developed. In these candidates, $[^{11}C]AFM$ and $[^{11}C]DASB$ showed high binding affinity to serotonin transporter and fast in vivo kinetics. This paper gives an overview of current status on dopamine and serotonin transporter imaging radiopharmaceuitcals and the development of new lead compounds as potential radiopharmaceuticals by medicinal chemistry.

• Journal of Pharmaceutical Investigation
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• 제40권6호
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• pp.321-332
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• 2010

Growing interest in the nasal route as a drug delivery system calls for a reliable in vitro model which is crucial for efficiently evaluating drug transport through the nasal cells. Various in vitro cell culture systems has thus been developed to displace the ex vivo excised nasal tissue and in vivo animal models. Due to species difference, results from animal studies are not sufficient for estimating the drug absorption kinetics in humans. However, the difficulty in obtaining reliable human tissue source limits the use of primary culture of human nasal epithelial cells. This shortage of human nasal tissue has therefore prompted studies on the "passage" culture of nasal epithelial cells. A serially passaged primary human nasal epithelial cell monolayer system developed by the air-liquid interface (ALI) culture is known to promote the differentiation of cilia and mucin gene and maintain high TEER values. Recent studies on the in vitro nasal cell culture systems for drug transport studies are reviewed in this article.

• 대한치과교정학회지
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• 제22권2호
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• pp.309-325
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• 1992

The purpose of this study was to evaluate the effect of intrinsic factor and extrinsic factor for growth of the mandibular condylar cartilage of 4 day-old rats in a serum-free medium for 1, 4, 7, 14 days. They were compared with normal growth in vivo and with growth of spheno-occipital synchondrosis in serum-free medium. The cellular kinetics of cartilages were evaluated by auto-radiography of tritiated thymidine. 1. Condylar cartilage was enlarged with rounded head on day 14 of experiment while in vivo the rounded-headed shape changed into functionally flattened appearance. 2. On day 14 of experiment, a severe reduction of the proliferative zone and a considerable increase of the hypertrophic zone were observed while in normal control group endochondrol bone formation and bone marrow were observed. 3. The proliferative activity in the proliferative zone of condylar cartilage detected by $^3H-thymidine$ incorporation was lower than that of normal control group and decreased more than that of spheno-occipital synchondrosis, but it continued during the 14 days of culture. 4. The continued maintenance of condylar cartilage and morphologic change were disturbed in this culture system, but cell division within the proliferative zone was continued and probably linked to intrinsic factor.

• Restorative Dentistry and Endodontics
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• 제47권4호
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• pp.42.1-42.11
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• 2022

Objective: This study investigated the effects of various concentrations of sodium hypochlorite (NaOCl) on human whole-blood clotting kinetics, the structure of the blood clots formed, and transforming growth factor (TGF)-β1 release. Materials and Methods: Human whole blood was collected from 5 healthy volunteers and divided into 4 groups: CG (control, 0.5 mL of blood), BN_0.5 (0.5 mL of blood with 0.5 mL of 0.5% NaOCl), BN₃ (0.5 mL of blood with 0.5 mL of 3% NaOCl), and BN_5.25 (0.5 mL of blood with 0.5 mL of 5.25% NaOCl). The effects of NaOCl on clotting kinetics, structure of fibrin and cells, and release of TGF-β1 were assessed using thromboelastography (TEG), scanning electron microscopy (SEM), and enzyme-linked immunosobent assay, respectively. Statistical analysis was conducted using the Kruskal Wallis and Mann-Whitney U tests, followed by the post hoc Dunn test. A p value < 0.05 indicated statistical significance. Results: The blood samples in BN_0.5 and BN₃ did not clot, whereas the TEG of BN_5.25 showed altered clot formation. Samples from the CG and BN₃ groups could only be processed with SEM, which showed that the latter lacked fibrin formation and branching of fibers, as well as clumping of red blood cells with surface roughening and distortion. TGF-β1 release was significantly highest in BN₃ when all groups were compared to CG (p < 0.05). Conclusions: Each concentration of NaOCl affected the release of TGF-β1 from blood clots and altered the clotting mechanism of blood by affecting clotting kinetics and cell structure.

• Translational and Clinical Pharmacology
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• 제26권3호
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• pp.115-117
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• 2018

This tutorial explains the basic principles of mechanistic ligand-receptor interaction model, which is an operational model of agonism. A growing number of agonist drugs, especially immune oncology drugs, is currently being developed. In this tutorial, time-dependent ordinary differential equation for simple $E_{max}$ operational model of agonism was derived step by step. The differential equation could be applied in a pharmacodynamic modeling software, such as NONMEM, for use in non-steady state experiments, in which experimental data are generated while the interaction between ligand and receptor changes over time. Making the most of the non-steady state experimental data would simplify the experimental processes, and furthermore allow us to identify more detailed kinetics of a potential drug. The operational model of agonism could be useful to predict the optimal dose for agonistic drugs from in vitro and in vivo animal pharmacology experiments at the very early phase of drug development.

• Journal of Pharmaceutical Investigation
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• 제18권4호
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• pp.187-195
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• 1988

Poorly permeable $Eudragit^{\circledR}$ RS 100 polymer was used as a wall material for the microencapsulation of zipeprol dihydrochloride by a phase separation method from chloroform-cyclohexane system with 5% polyisobutylene in cyclohexane, and microcapsules obtained were evaluated in vitro by particle size analysis, scanning electron microscopy, drug release test and in vivo bioavailability test in rats. The mechanism of drug release from microcapsules appeared to fit Higuchi matrix model kinetics. The area under the first moment of plasma concentration-time curve of the microcapsules obtained was considerably increased (p<0.05) as compared with that from zipeprol dihydrochloride oral solution. Therefore, it may be suggested that $Eudragit^{\cirledR}$ RS 100 coated zipeprol dihydrochloride microcapsules can be used as a sustained release medication.