• Journal of Pharmaceutical Investigation
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• v.40 no.1
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• pp.15-21
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• 2010

Sibutramine is an orally administered centrally-acting antiobesity agent and inhibits both noradrenaline(norephinephirine) and serotonin(5-HT) reuptake. These effects are contributed by its active metabolites, M1 and M2. However, as the free base form of sibutramine is an oil form in room temperature, it had the problem of handling and stability. Thus, this drug should be used in the form of acid salt form in the pharmaceutical application. Unfortunately, anhydrous sibutramine hydrochloride is highly hygroscopic and unstable. In order to solve the hygroscopicity of the anhydrous salt form, another sibutramine acid salt form must be developed as a hydrate form. In this study. to overcome these problems, various of sibutramine acid salt forms were prepared with the pharmaceutically available salts such as maleate, esylate, mandelate, camsylate, besylate, salicylate, tartrate, isethionate and malate forms, and their physicochemical properties were investigated. Sibutramine malate was selected for excellent solubility and stability among the listed salt forms above. Its pharmacokinetic parameters were evaluated in rats comparing with sibutramine HCl, resulting in similar parameters. In vitro dissolution study of sibutramine malate-loaded capsule was performed comparison with commercial product ($Reductil^{(R)}$) in pH 1.2, pH 4.0, pH 6.8 and water medium. Our results indicated that there were no significant differences in their dissolution profiles were similar in all tested medium. Thus, sibutramine malate-loaded capsule should be a potential candiate due to its excellent solubility, good stability and biosimilar absorption.

• Biomolecules & Therapeutics
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• v.19 no.2
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• pp.248-254
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• 2011

Biotransformation of pharmacologically inactive lactone prodrug simvastatin (SV) into pharmacologically active simvastatin ${\beta}$-hydroxy acid (SVA) exhibits inter-species differences due to variations in amount and activity of esterase enzymes. In this study, we investigated the pharmacokinetics (PK) of SV and its metabolite SVA following oral doses of SV from controlled-release (CR) tablets and immediate-release (IR) tablets in rodent and canine animal models that features different esterase activity. In rat PK study, no SV was detected in plasma for both formulations due to rapid hydrolysis of SV into SVA by plasma esterase. Besides, no significant differences in PK parameters of SV or SVA were observed between both species. In dog PK study, the relative oral bioavailability of CR tablets in terms of SV was 72.3% compared to IR tablets. Regarding formulation differences in dogs, CR tablets exhibited significantly lower $C_{max}$ (p<0.05), and higher $T_{max}$ (p<0.01) and MRT (p<0.01) for both SV and SVA compared to IR tablets. Accordingly, CR tablets of SV with prolonged drug release profiles in both species might be a potential candidate for a more effective delivery of SV with reduced side effects. Besides, similar PK parameters of SV and SVA in both species despite variation in enzyme activities suggested involvement of equally potent biotransformation pathways in these animal species.

• Journal of Society of Preventive Korean Medicine
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• v.17 no.1
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• pp.77-88
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• 2013

Objectives : This study was aim to evaluate effects of pharmacodynamics and toxicity in combination therapy of donepezil with Gongjindan. Methods : After 10mg/kg of donepezil treatment, Gongjindan 100mg/kg was administered within 5 min. The plasma were collected at 30min before administration, 30min, 1, 2, 3, 4, 6, 8 and 24hrs after end of Gongjindan treatment, and plasma concentrations of donepezil were analyzed using LC-MS/MS methods. PK parameters of donepezil were analysis as compared with donepezil single administered rats. Results : Gongjindan markedly inhibited the absorption of donepezil regardless of sample time, from 30min to 8hrs after end of co-administration comparing with donepezil single treated rats. Especially the absorption of donepezil was significantly decreased at 2hrs after co-administration as compared with donepezil single treated rats, in the present study. Accordingly, the Cmax(-27.76%), $AUC_{0-t}$(-27.22%) and $AUC_{0-inf}$(-26.54%) of donepezil in co-administered rats were significantly decreased as compared with donepezil single treated rats, respectively. Conclusions : Based on the results of the present study, co-administration of Gongjindan decreases the oral bioavailability of donepezil by inhibiting the absorption. It is considered that the more detail pharmacokinetic studies should betested to conclude the effects of Gongjindan on the pharmacokinetics of donepezil, when they were co-administered, like the effects after co-administration with reasonable intervals considering the Tmax of donepezil and after repeated co-administrations.

• Biomolecules & Therapeutics
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• v.25 no.6
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• pp.648-658
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• 2017

7-O-Succinyl macrolactin A (SMA) exerts several pharmacological effects including anti-bacterial, anti-inflammation, and anti-cancer activities. Recently, SMA has been extensively evaluated as an anti-cancer drug. Thus, the objectives of the present study were to characterise the pharmacokinetics of SMA via both non-compartmental and compartmental analysis in mice, rats, and dogs, and to derive an appropriate first-in-man dose based on allometric scaling of the animal data. The time courses of plasma SMA concentrations after intravenous administration to rats and dogs were analysed retrospectively, as were data collected after intraperitoneal SMA injection in mice. Pharmacokinetic parameters were estimated via both noncompartmental and compartmental analysis, and were correlated with body weight and/or the potential maximum life-span. The clearance and distribution volume of SMA in humans were predicted, and a first-in-man dose proposed. A two-compartment model best described the time courses of SMA plasma concentrations after a saturation elimination process was applied to fit the dataset obtained from rats. Incorporation of the maximum potential life-span during allometric scaling was required to improve the estimation of human clearance. The SMA clearance and the distribution volume in the steady state, in a 70-kg adult male, were estimated to be 30.6 L/h and 19.5 L, respectively. To meet the area under the curve (AUC) required for anti-tumour activity, a dose of 100 mg (~1.5 mg/kg) was finally proposed as the first dose for a 70-kg human. Although toxicological profiles derived from non-clinical studies must be considered before any final decision is made, our work will facilitate clinical studies on SMA.

• Biomolecules & Therapeutics
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• v.28 no.4
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• pp.311-319
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• 2020

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a newly emerging viral disease with fatal outcomes. However, no MERS-CoV-specific treatment is commercially available. Given the absence of previous structure-based drug discovery studies targeting MERS-CoV fusion proteins, this set of compounds is considered the first generation of MERS-CoV small molecule fusion inhibitors. After a virtual screening campaign of 1.56 million compounds followed by cell-cell fusion assay and MERS-CoV plaques inhibition assay, three new compounds were identified. Compound numbers 22, 73, and 74 showed IC₅₀ values of 12.6, 21.8, and 11.12 µM, respectively, and were most effective at the onset of spike-receptor interactions. The compounds exhibited safe profiles against Human embryonic kidney cells 293 at a concentration of 20 µM with no observed toxicity in Vero cells at 10 µM. The experimental results are accompanied with predicted favorable pharmacokinetic descriptors and drug-likeness parameters. In conclusion, this study provides the first generation of MERS-CoV fusion inhibitors with potencies in the low micromolar range.

• Biomolecules & Therapeutics
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• v.26 no.5
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• pp.494-502
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• 2018

Breast cancer is currently the most prevalent cancer in women, and its incidence increases every year. Azole antifungal drugs were recently found to have antitumor efficacy in several cancer types. They contain an imidazole (clotrimazole and ketoconazole) or a triazole (fluconazole and itraconazole) ring. Using human breast adenocarcinoma cells (MCF-7 and MDA-MB-231), we evaluated the effects of azole drugs on cell proliferation, apoptosis, cell cycle, migration, and invasion, and investigated the underlying mechanisms. Clotrimazole and ketoconazole inhibited the proliferation of both cell lines while fluconazole and itraconazole did not. In addition, clotrimazole and ketoconazole inhibited the motility of MDA-MB-231 cells and induced $G_1$-phase arrest in MCF-7 and MDA-MB-231 cells, as determined by cell cycle analysis and immunoblot data. Moreover, Transwell invasion and gelatin zymography assays revealed that clotrimazole and ketoconazole suppressed invasiveness through the inhibition of matrix metalloproteinase 9 in MDA-MB-231 cells, although no significant changes in invasiveness were observed in MCF-7 cells. There were no significant changes in any of the observed parameters with fluconazole or itraconazole treatment in either breast cancer cell line. Taken together, imidazole antifungal drugs showed strong antitumor activity in breast cancer cells through induction of apoptosis and $G_1$ arrest in both MCF-7 and MDA-MB-231 cells and suppression of invasiveness via matrix metalloproteinase 9 inhibition in MDA-MB-231 cells. Imidazole drugs have well-established pharmacokinetic profiles and known toxicity, which can make these generic drugs strong candidates for repositioning as antitumor therapies.

• Korean Journal of Veterinary Research
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• v.39 no.2
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• pp.267-275
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• 1999

Bovine somatotropin is known to improve the growth rate and lactation in cattle. In this study, we examined the concentration-time profiles of a sustained-release formulation of bovine somatotropin (BST) and insulin-like growth factor-1 (IGF-1) in plasma and milk in cows. In addition, the possible effect of co-administrated vitamin ADE complex on the pharmacokinetic parameters of BST and IGF-1 was evaluated. 1. Plasma BST and IGF-1 levels reached the peak at 12~24 and 48 hours after the administration of BST, and plasma half-lives ranged 100 to 137 and 201 to 310 hours, respectively. To 8th day after administration, BST and IGF-1 levels in milk were not significantly different from the control levels. 2. Plasma BST levels showed cyclic pattern with high concentrations in early stage after each injection and following gradual declining during repeated administrations at 2 week intervals, while plasma IGF-1 levels in treated animals did not show such a cyclic pattern, but remained higher than the control levels. 3. Milk BST and IGF-1 levels during repeated treatments were not significantly different from the control levels. 4. Co-administration of vitamin ADE complex yielded slightly increased AUC of plasma BST for high dose group, but such effect was not evident in the IGF-1 levels. Co-administration of ADE complex tended to increase plasma BST levels and decrease the elimination half-life of IGF-1. 5. These results suggest that the BST formulation tested is one of the ideal sustained-release formulation for long term use in dairy industry. As for the co-administration of vitamin ADE complex, the benefit of co-administration with BST is needed to be further evaluated.

• Journal of Pharmaceutical Investigation
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• v.28 no.2
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• pp.73-80
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• 1998

In order to elucidate the effect of N-demethylation on the in vivo metabolite kinetics, especially hepatic first-pass effect of trimebutine(TMB), the N-demethylation of TMB to N-monodesmethyl trimebutine(N-TMB) was studied in rats. TMB(10 mg/kg) and N-TMB(10 mg/kg) were injected into the femoral and the portal vein, respectively. And the pharmacokinetic parameters were obtained from the plasma concentration-time profiles of TMB and N-TMB determined by the simultaneous analysis using high-performance liquid chromatography. It was supposed that these drugs were almost metabolized in vivo because the urinary and biliary excreated amounts of TMB and N-TMB were lower than 0.1% of the administered dose. According to the hepatic biotransformation model and metabolic pathways of TMB proposed, it was found that the fraction of systemic clearance of TMB which formed N-TMB in liver$(G_{mi})$ was 0.826, that of TMB which furnishes the available N-TMB to the systemic circulation$(F_{mi})$ was 0.083, and the absolute hepatic bioavailability of N-TMB formed trom TMB$(F_{mi.p})$ was 0.1. These results showed that TMB was suspected of the sequential hepatic first-pass metabolism and N-demethylated by 82.6%. Therefore, the residue would be hydrolyzed by the esterase in the liver. That is, the ability of N-demethylation of TMB was 4.75-fold larger than that of hydrolysis by the esterase in rats.

• Journal of Pharmaceutical Investigation
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• v.28 no.4
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• pp.275-282
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• 1998

In order to develop a desirable in vitro release which correlates well with in vivo bioavailability, hollow type suppository containing Propranolol HCl(PPH) powder in the cavity and conventional type suppository with dispersed PPH in the base were prepared. Polyvinyl alcohol (PVA) hydrogel as a base and PPH as a model drug were used for the preparation of suppository. The rates of drug release from the suppositories were studied by Paddle method, Muranish method, Dialysis tubing method and Rotating dialysis cell method. The release profiles from suppositories using the four different release tests were compared. After a rectal administration in rat, the mean $C_{max}$ of hollow type suppository was significantly lower than that of conventional type, but $T_{max}$, $AUC_{0{\to}12}$ and MRT of hollow type were significantly higher 1.6 times, 1.2 times and 1.9 times than those of conventional type, respectively. The computer program was used to simulate plasma concentration from in vitro released amounts of drug and in vivo pharmacokinetic parameters. Based on comparison of the simulated bioavailability from computer program with experimental bioavailability in rat we have found out in vitro release test which correlates well with in vivo bioavailability. Our results have shown the best correlation between in vitro release and in vivo bioavailability in PPH-PVA hydrogel hollow type suppository for the paddle method and conventional type suppository for the rotating dialysis cell method. In this work we propose that PPH-PVA hydrogel suppository shows in vitro-in vivo correlation. This data should help to optimize the formulation of the drug and provide a basis for quality control procedures.

• Journal of Pharmaceutical Investigation
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• v.22 no.3
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• pp.205-210
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• 1992

In order to develop a controlled-release oral drug delivery system (DDS) of theophylline (TP), microporous membrane-coated tablets were prepared and evaluated in vitro and in vivo. Rapidly water-soluble core tablets of TP (300 mg) were prepared by wet granulation and compression technique, Then the core tablets were spray-coated with polyvinylchloride (PVC) in which micronized sucrose particles were dispersed. Effect of formula compositions of coating suspensions on the pharmaceutical characteristics such as membrane strength and dissolution was investigated in vitro. The membranes remained unbroken in pH 1.2 buffer at $37^{\circ}C$ at least for 2 hours after the disintergration test. TP was released from the coated-released tablets at a zero-order rate over 8 hours. The release at pH 1.2 and 4.0 was similar in rate but a little more rapid than that at pH 6.8. The coated tablets were administered to three healthy male volunteers and their saliva profiles of TP were compared with those from the commercial sustained release TP tablets such as Slobid and Asconthin. Saliva TP concentrations from the coated tablets were successfully sustained over 48 hours after the dosing and were comparable to those of the commercial sustained-release tablets. The membrane-coating technique is very simple and does not need any sophisticated equipments. In this respect, the membrane-coated tablets may be superior to the commercial sustained-release tablets and this technique is worth adopting by the pharmaceutical industries.