• Journal of Pharmaceutical Investigation
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• 제25권4호
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• pp.323-330
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• 1995

Ceftezole pivaloyloxymethyl ester(CFZ-PV) was synthesized to improve oral absorption and bioavailability of parent drug by esterification of ceftezole(CFZ) with chloromethyl pivalate. The successful synthesis of CFZ-PV was conformed by spectroscopic analysis. Partition coefficient studies showed that CFZ-PV is more lipophillic than CFZ. The pharmacokinetic characteristics of CFZ-PV and CFZ were compared following oral administrations of these compounds to rabbits. The amount of CFZ in plasma was determined with an HPLC method. The ester compound (prodrug) was not detected in plasma following oral administration of CFZ-PV, and although CFZ-PV had not microbiological activity in vitro, the plasma taken after oral administration of CFZ-PV had microbiological activity. From above observations, it was noted that CFZ-PV is rapidly hydrolyzed to CFZ in the body. And the oral absorption of CFZ-PV was increased by yielding 2-fold bioavailability rather than CFZ. Therefore, CFZ-PV could be a novel prodrug of CFZ which can improve the oral bioavailability of CFZ.

• Journal of Pharmaceutical Investigation
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• 제22권2호
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• pp.139-148
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• 1992

A prodrug of cefazolin pivaloyloxymethyl ester (CFZ-PV) was synthesized to improve oral absorption and bioavailability of parent drug by esterification of sodium cefazolin (CFZ) with chloromethyl pivalate. The successful synthesis of CFZ-PV was confirmed by spectroscopic analysis. Partition coefficient studies showed that CFZ-PV is more lipophilic than CFZ. The pharmacokinetic characteristics of CFZ-PV and CFZ preparations were compared following oral administrations of these compounds to rabbits. The analysis of CFZ in plasma was conducted by HPLC method. The ester compound (prod rug) was not detected in plasma following oral administration of CFZ-PV, and although CFZ-PV had not microbiological activity in vitro, the plasma taken after CFZ-PV administration had microbiological activity. From above observations, it was noted that CFZ-PV is rapidly hydrolyzed to CFZ in the body. And it was found that the oral absorption of CFZ-PV was increased, yielding 2-fold higher bioavailability than CFZ. From the results of this experiment, it was concluded that CFZ-PV could be a novel prodrug of CFZ which can improve the oral bioavailability of CFZ.

• 한국임상약학회지
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• 제3권1호
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• pp.61-70
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• 1993

A new cephalosporin derivate, cefazolin phthalidyl ester(CFZ-PT) was synthesized to improve oral absorption and bioavailability of parent drug by esterification of sodium cefazolin(CFZ). Partition coefficient studies showed that CFZ-PR is more lipophilic than CFZ. The pharmacokinetic characteristics of CFZ-PT and CFZ preparations were compared following oral administrations of these compounds to rabbits. The analysis of CFZ in plasma was conducted by HPLC method. The ester compound was not detected in plasma following oral administration of CFZ-PT was increased by yielding 3.5-fold bioavailability rather than CFZ. From the results of this experiment, it was concluded that CFZ-PT could be a novel prodrug of CFZ which can improve the oral bioavailability of CFZ.

• 대한약학회:학술대회논문집
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• 대한약학회 2005년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.184-186
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• 2005

• Biomolecules & Therapeutics
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• 제19권3호
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• pp.364-370
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• 2011

The purpose of this study was to investigate the effects of curcumin on the pharmacokinetics of loratadine in rats. The effect of curcumin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Pharmacokinetic parameters of loratadine were also determined after oral and intravenous administration in the presence or absence of curcumin. Curcumin inhibited CYP3A4 activity with an IC50 value of 2.71 ${\mu}M$ and the relative cellular uptake of rhodamine-123 was comparable. Compared to the oral control group, curcumin significantly increased the area under the plasma concentration-time curve and the peak plasma concentration by 39.4-66.7% and 34.2-61.5%. Curcumin also significantly increased the absolute bioavailability of loratadine by 40.0-66.1% compared to the oral control group. Consequently, the relative bioavailability of loratadine was increased by 1.39- to 1.67-fold. In contrast, curcumin had no effect on any pharmacokinetic parameters of loratadine given intravenously, implying that the enhanced oral bioavailability may be mainly due to increased intestinal absorption caused via P-gp and CYP3A4 inhibition by curcumin rather than to reduced renal and hepatic elimination of loratadine. Curcumin enhanced the oral bioavailability of loratadine in this study. The enhanced bioavailability of loratadine might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and reduced fi rst-pass metabolism of loratadine via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by curcumin.

• 대한본초학회지
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• 제33권5호
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• pp.19-37
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• 2018

Objectives : Oryeong-san was composed of Alismatis Rhizoma, Atractylodis Rhizoma Alba, Poria Sclerotium, Polyporus, Cinnamomi Cortex, and known to have hundreds of chemical compounds. The aim of this study was to screen chemical compounds constituting Oryeong-san with the drug-likeness and oral bioavailability from the analysis of their physicochemical properties. Methods : A list of chemical compounds of Oryeong-san was obtained from TM-MC(database of medicinal materials and chemical compounds in Northeast Asian traditional medicine). To remove redundant compounds, the SMILES (Simplified Molecular Input Line Entry System) strings of each compound were identified. All of the physicochemical properties for the compounds were calculated using the DruLiTo(Drug Likeness Tool). Drug-likeness was estimated by QED(Quantitative Estimate of Druglikeness) and OB(Oral bioavailability) was checked based on the Veber's rules. Results : A total of 475 compounds were obtained by eliminating duplication among 544 compounds of 5 medicinal materials. Analysis of the physicochemical properties revealed that the most common values were MW(molecular weight) 200~300 g/mol, ALOGP(octanol-water partition coefficient) 1~2, HBA(number of hydrogen bond acceptors) 0~1, HBD(number of hydrogen bond donors) 0, PSA(polar surface area) 0~50 angstrom, ROTB(number of rotatable bonds) 1, AROM(number of aromatic rings) 0, and ALERT(number of structural alerts) 1. QED had 93% of the values between 0.2 and 0.7, and OB had 90% of the value of TRUE. Conclusions : We in this paper screened the candidate active compounds of Oryeong-san using the QED and Veber's rules. In the future, we will use the screening results to analyze the mechanism of Oryeong-san based on systems pharmacology.

• Biomolecules & Therapeutics
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• 제25권4호
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• pp.452-459
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• 2017

In this study, the effect of particle size of genistein-loaded solid lipid particulate systems on drug dissolution behavior and oral bioavailability was investigated. Genistein-loaded solid lipid microparticles and nanoparticles were prepared with glyceryl palmitostearate. Except for the particle size, other properties of genistein-loaded solid lipid microparticles and nanoparticles such as particle composition and drug loading efficiency and amount were similarly controlled to mainly evaluate the effect of different particle sizes of the solid lipid particulate systems on drug dissolution behavior and oral bioavailability. The results showed that genistein-loaded solid lipid microparticles and nanoparticles exhibited a considerably increased drug dissolution rate compared to that of genistein bulk powder and suspension. The microparticles gradually released genistein as a function of time while the nanoparticles exhibited a biphasic drug release pattern, showing an initial burst drug release, followed by a sustained release. The oral bioavailability of genistein loaded in solid lipid microparticles and nanoparticles in rats was also significantly enhanced compared to that in bulk powders and the suspension. However, the bioavailability from the microparticles increased more than that from the nanoparticles mainly because the rapid drug dissolution rate and rapid absorption of genistein because of the large surface area of the genistein-solid lipid nanoparticles cleared the drug to a greater extent than the genistein-solid lipid microparticles did. Therefore, the findings of this study suggest that controlling the particle size of solid-lipid particulate systems at a micro-scale would be a promising strategy to increase the oral bioavailability of genistein.

• Journal of Pharmaceutical Investigation
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• 제23권3호
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• pp.139-144
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• 1993

Microencapsulation of acyclovir, an effective antiviral agent which acts as a specific inhibitor of herpes DNA polymerase, by carbopol-gelatin complex coacervation has been carried out to develop an oral controlled release preparation, which could improve the absorption characteristics in GI tract. After dissolving carbopol and gelatin separately in distilled water at $40^{\circ}C$, gelatin solution was mixed with carbopol solution while stirring at the same temperature. The pH of the mixture was lowered gradually by dropwise addition of 10% HCI with continuous stirring, and then, at pH 3.5, positively charged gelatin molecules were attracted to negatively charged carbopol. These coacervation processes were observed by optical microscopy during preparation. Plasma concentrations of acyclovir in rats after an oral administration of microcapsule suspension were assayed by HPLC, and pharmacokinetic parameters were calculated based on the model-independent analyses. Two standard formulations, oral solution and intravenous bolus injection, were used as references to compare the bioavailability. It has been revealed that $C_{max}$, $T_{max}$, and MRT of microcapsule suspension were greater than those of oral solution, which results in about two-fold increases in bioavailability. Therefore, in conclusion, the carbopol-gelatin microcapsule of acyclovir might be evaluated as an effective oral controlled release preparation which could increase the bioavailability of acyclovir.

• Archives of Pharmacal Research
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• 제26권1호
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• pp.89-94
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• 2003

In vivo clearance of BMS-182874 was primarily due to metabolism via stepwise N-demethylation. Despite in vivo clearance approached ca 50％ of the total liver plasma flow, BMS-182874 was completely bioavailable after oral administration in rats. Saturable first-pass metabolism and the role of extrahepatic tissue were evaluated as possible reasons for complete oral bioavailability despite extensive metabolic clearance. Pharmacokinetic parameters were obtained after an intravenous and a range of oral doses of BMS-182874 in rats. Bile and urine were collected from bile-duct cannulated (BDC) rats and the in vivo metabolic pathways of BMS-182874 were evaluated. Pharmacokinetics of BMS-182874 were also compared in nephrectomized (renally impaired) vs. sham-operated control rats. Oral bioavailability of BMS-182874 averaged 100％, indicating that BMS-182874 was completely absorbed and the first-pass metabolism (liver or intestine) was negligible. The AUC and C/sub max/ values increased dose-proportionally, indicating kinetics were linear within the oral dose range of 13 to 290 mmole/kg. After intravenous administration of BMS-182874 to BDC rats, about 2％ of intact BMS-182874 was recovered in excreta, indicating that BMS-182874 was cleared primarily via metabolism in vivo. The major metabolite circulating in plasma was the mono-N-desmethyl metabolite and the major metabolite recovered in excreta was the di-N-desmethyl metabolite. In vivo clearance of BMS-182874 was significantly reduced in nephrectomized rats. These observations suggest saturable first-pass metabolism is unlikely to be a mechanism for complete oral bioavailability of BMS-182874. Reduced clearance observed in the nephrectomized rats suggests that extrahepatic tissues (e.g., kidneys) may play an important role in the in vivo clearance of xenobiotics that are metabolized via N-demethylation.

• Journal of Pharmaceutical Investigation
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• 제23권2호
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• pp.61-69
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• 1993

Prodrug of cefazolin (CFZ) was prepared with the objective of improving its oral bioavailability. Cefazolin phthalidyl ester (CFZ-PT) was synthesized and evaluated as potential prodrug form. The successful synthesis of CFZ-PT was identified by spectroscopic analysis. Partition coefficient studies showed that CFZ-PT is more lipophilic than CFZ and the ester was hydrolyzed enzymatically into the parent drug in blood, liver and intestinal homogenates. The pharmacokinetic characteristics of CFZ-PT and CFZ were compared following oral administrations to rabbits. Serum CFZ concentration was determined by HPLC method and the ester compound (prodrug) was not detected in serum following oral administration of CFZ-PT. CFZ-PT did not have antimicrobial activity in vitro against Bacillus subtilis ATCC 6633, whereas CFZ-PT in serum after oral administration to rabbits had antimicrobial activity. From above observations, it was noted that CFZ-PT is rapidly hydrolyzed to CFZ in the body and the bioavailability of CFZ-PT was increased by 3.5-fold than that of CFZ. From these results of this study, it was concluded that CFZ-PT may be a novel prodrug of CFZ which can improve the oral absorption of CFZ.