• 농약과학회지
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• 제18권4호
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• pp.342-349
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• 2014

미국, EU, 한국의 농작업자위해성평가를 위한 AOEL 설정, 국가별 경구흡수율 적용, 노출량 산출방법을 조사하였다. 농약성분 141종에 대한 경구흡수율을 조사하였으며 경구흡수율을 적용한 농작업자노출허용량(AOEL)과 국내 설정 AOEL을 이용하여 농작업자위해성평가를 실시하였다. 미국과 EU에서는 external dose를 internal dose로 변환하기 위하여 경구흡수율 또는 피부흡수율을 적용하였으나 한국에서는 AOEL 설정 시 경구흡수율을 적용하지 않은 external dose를 사용하였다. 141종의 농약성분 중 50종이 경구흡수율 80% 미만이었으며 경구흡수율을 적용하는 경우 약 36%의 농약성분이 이전 AOEL보다 낮아질 것으로 사료되었다. 50종의 농약성분 중 한국에 등록된 농약 28품목에 대해 EU AOEL을 이용하여 농작업자위해성평가를 실시한 결과, chlorothalonil WG 등 12품목이 독성노출비가 1 이하로 계산되어 위해성이 높은 것으로 나타났다. 또한 50종 중 한국 AOEL이 설정되어 있으며 한국에 등록된 농약 24품목에 대해 한국 AOEL을 이용하여 농작업자위해성평가를 실시한 결과, chlorothalonil WG 등 6품목은 독성노출비가 1 이하로 위해성이 높게 나타났다. 한국 AOEL이 없는 4품목에 대해 EU AOEL을 경구흡수율 100%로 환산한 수치를 이용하여 위해성평가를 실시한 결과, daminozide WP 등 4품목 모두 독성노출비 1 초과로 위해성이 낮게 나타났다. 경구흡수율 적용 및 미적용 EU AOEL과 한국 AOEL을 사용한 농작업자위해성평가를 비교한 결과 oxadiagyl SC 등 6품목을 제외한 22품목에서 동일한 위해성평가 결과가 나타났다. 본 연구 결과, 농작업자 위해성 평가를 실시할 때 경구흡수율을 적용한 AOEL을 이용할 수 있을 것으로 사료되었다. 경구흡수율을 적용한 AOEL 설정 및 이용한 농작업자위해성평가를 수행하였을 때 보다 실제에 가까운 평가방법으로 판단되므로 등록농약의 평가에 적용될 수 있도록 개선이 필요할 것으로 사료된다.

• Bulletin of the Korean Chemical Society
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• 제32권11호
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• pp.3967-3972
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• 2011

A whole body physiologically based pharmacokinetic (PBPK) model was applied to investigate absorption, distribution, and physiologic variations on pharmacokinetics of imatinib in human body. Previously published pharmacokinetic data of the drug after intravenous (i.v.) infusion and oral administration were simulated by the PBPK model. Oral dose absorption kinetics were analyzed by adopting a compartmental absorption and transit model in gut section. Tissue/plasma partition coefficients of drug after i.v. infusion were also used for oral administration. Sensitivity analysis of the PBPK model was carried out by taking parameters that were commonly subject to variation in human. Drug concentration in adipose tissue was found to be higher than those in other tissues, suggesting that adipose tissue plays a role as a storage tissue for the drug. Variations of metabolism in liver, body weight, and blood/plasma partition coefficient were found to be important factors affecting the plasma concentration profile of drug in human body.

• Macromolecular Research
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• 제17권2호
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• pp.79-83
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• 2009

The oral delivery of heparin is the preferred therapy in the treatment of patients with a high risk of deep vein thrombosis and pulmonary embolism. New conjugates of heparin and sodium deoxycholate were synthesized in order to enhance the heparin absorption in the GI tract. After oral administration of DOC-heparin, the concentration in anti-FXa assay was increased with increasing amount of coupled DOC. The maximum concentration of DOC-heparin VIII conjugate was $3.3{\pm}0.5\;IU/mL$ at an oral dose of 10 mg/kg, which was 3-fold higher than the baseline level. Finally, DOC coupled to heparin greatly enhanced the absorption of heparin in the GI tract, and this enhancing effect was not induced by changing the tissue structure of the GI wall.

• Archives of Pharmacal Research
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• 제25권5호
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• pp.572-584
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• 2002

Rapid development in molecular biology and recent advancement in recombinant technology increase identification and commercialization of potential protein drugs. Traditional forms of administrations for the peptide and protein drugs often rely on their parenteral injection, since the bioavailability of these therapeutic agents is poor when administered nonparenterally. Tremendous efforts by numerous investigators in the world have been put to improve protein formulations and as a result, a few successful formulations have been developed including sustained-release human growth hormone. For a promising protein delivery technology, efficacy and safety are the first requirement to meet. However, these systems still require periodic injection and increase the incidence of patient compliance. The development of an oral dosage form that improves the absorption of peptide and especially protein drugs is the most desirable formulation but one of the greatest challenges in the pharmaceutical field. The major barriers to developing oral formulations for peptides and proteins are metabolic enzymes and impermeable mucosal tissues in the intestine. Furthermore, chemical and conformational instability of protein drugs is not a small issue in protein pharmaceuticals. Conventional pharmaceutical approaches to address these barriers, which have been successful with traditional organic drug molecules, have not been effective for peptide and protein formulations. It is likely that effective oral formulations for peptides and proteins will remain highly compound specific. A number of innovative oral drug delivery approaches have been recently developed, including the drug entrapment within small vesicles or their passage through the intestinal paracellular pathway. This review provides a summary of the novel approaches currently in progress in the protein oral delivery followed by factors affecting protein oral absorption.

• Archives of Pharmacal Research
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• 제8권3호
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• pp.177-186
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• 1985

Effect of food on the absorption characteristics of oral rifampicin was studied in the fasted rats. Rifampicin dissolved in a new cosolvent was also injected to the rats intravenously, and the pharmacokinetic analysis was performed to explain the effect of food on the gastrointestinal absorption of rifampicin. Rifampicin was absorbed rapidly and completely in the fasting state. Food had a profound effect on the gastrointestinal absorption of rifampicin, i. e., bioavailability and the extent of absorption were decreased to less than one-third of the fasting state in the postprandial state. Food seemed to imhibit the absorption and reabsorption of rifampicin in the gastrointestinal tract, but not the absorption rate constant. Hepatobiliary excretion seemed to be the major route of elimination, since the renal clearance accounted for only 8 % of the systemic clearance. Nevertheless, first-pass effect was negligibly small and most of rifampicin absorbed could reach systemic circulation. Serum concentration change of oral rifampicin on multiple dosing differed markedly in the fasting and postprandial state, which suggested the need of careful adjustment of dosage regimen in both states.

• Archives of Pharmacal Research
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• 제26권9호
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• pp.768-772
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• 2003

Tween 80 (Polysorbate 80) is a hydrophilic nonionic surfactant commonly used as an ingredient in dosing vehicles for pre-clinical in vivo studies (e.g., pharmacokinetic studies, etc.). Tween 80 increased apical to basolateral permeability of digoxin in Caco-2 cells suggesting that Tween 80 is an in vitro inhibitor of P-gp. The overall objective of the present study was to investigate whether an inhibition of P-gp by Tween 80 can potentially influence in vivo absorption of P-gp substrates by evaluating the effect of Tween 80 on the disposition of digoxin (a model P-gp substrate with minimum metabolism) after oral administration in rats. Rats were dosed orally with digoxin (0.2 mg/kg) formulated in ethanol (40％, v/v) and saline mixture with and without Tween 80 (1 or 10％, v/v). Digoxin oral AUC increased 30 and 61％ when dosed in 1 ％ and 10％ Tween 80, respectively, compared to control (P＜0.05). To further examine whether the increase in digoxin AUC after oral administration of Tween 80 is due, in part, to a systemic inhibition of digoxin excretion in addition to an inhibition of P-gp in the GI tract, a separate group of rats received digoxin intravenously (0.2 mg/kg) and Tween 80 (10％ v/v) orally. No significant changes in digoxin IV AUC was noted when Tween 80 was administered orally. In conclusion, Tween 80 significantly increased digoxin AUC and Cmax after oral administration, and the increased AUC is likely to be due to an inhibition of P-gp in the gut (i.e., improved absorption). Therefore, Tween 80 is likely to improve systemic exposure of P-gp substrates after oral administration. Comparing AUC after oral administration with and without Tween 80 may be a viable strategy in evaluating whether oral absorption of P-gp substrates is potentially limited by P-gp in the gut.

• Archives of Pharmacal Research
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• 제25권3호
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• pp.387-391
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• 2002

The oral absorption and disposition of itraconazole were studied in rats, rabbits and dogs. Serum levels of itraconazole and its active metabolite, hydroxyitraconazole, were determined by a validated HPLC method. The absorption of itraconazole was relatively rapid in rats and dogs but was slower in rabbits. The terminal elimination half-life ($T_{1/2,{\lambda}z}$), time to the peak concentration ($T_{max}$), dose and weight normalized area under the curve (AUC) and the peak concentration ($C_{max}$) of itraconazole found in the dog were comparable to those reported in humans. As in humans, the metabolite to parent drug AUC ratios in rats and dogs were greater than unity but was less in rabbits. The dog appears to be an appropriate animal model while the rat, not the rabbit, may be used as an alternative animal model in predicting the oral absorption of itraconazole in humans.

• Journal of Pharmaceutical Investigation
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• 제16권4호
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• pp.148-151
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• 1986

This paper was designed to investigate the influence of different suppository bases on both the rectal absorption and dissolution rate of lithium carbonate, and to compare bioavailability from rectal administration with that from oral administration. The dissolution rates were in such order as PEG 4000, surfactant A (Witepsol 15+sodium lauryl sulfate), surfactant B (Witepsol 15+cholic acid), Witepsol 15 and cacao butter. Among various suppository bases, the blood level of lithium carbonate after rectal administration was increased in the following order: surfactant A>surfactant B>PEG 4000>Witepsol 15>cacao butter. When it comes to compare oral with rectal administration in AUC values, surfactants and PEG 4000 showed similar blood levels to oral administration, but lipophilic bases such as Witepsol 15 and cacao butter showed far lower blood level than oral administration. Peak time in oral administration was 2 hrs, but those in rectal administration using various suppository bases were $6{\sim}8$ hrs.

• Bulletin of the Korean Chemical Society
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• 제35권11호
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• pp.3188-3194
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• 2014

Compound K (CK) was formulated as polymeric micelles (PM) using Pluronic$^{(R)}$ F-127 to enhance the oral absorption of CK, an intestinal bacterial metabolite of ginseng protopanaxadiol saponin. The physicochemical properties of Ck-loaded PM were characterized and an in vitro transport study using the Caco-2 cell system as well as an in vivo pharmacokinetic study using SD rats was carried out. The hydrodynamic mean particle size of CK-loaded PM (CK-PM) was $254{\pm}23.45nm$ after rehydration and the drug loading efficiency was ca. 99.9%. The FT-IR spectroscopy, X-ray diffraction, differential scanning calorimetry and scanning electron microscopy data supported the presence of a new solid phase in the PM. The $P_{app}$ value of in vitro Caco-2 cell permeation of CK-PM and the oral absorption of CK was enhanced about 1.2-fold and 2.6-fold compared to CK suspension, respectively, showing that the present PM formulation enabled an enhancement of oral CK absorption.

• Archives of Pharmacal Research
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• 제18권6호
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• pp.427-433
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• 1995

A microscopic mass balance approach has hsown that the initial saturation (Is), absorption number (An), dose number (Do), and dissolution number (Dn) are four fundamental dimensionless parameters that can be used to estimate the fraction dose absorbed (F)l of suspensions of poorly soluble drugs in humans. The dissolution number of a drug increases with decreasing its particle size. The effect of micronization on F for suspensions was investigated in terms of Dn. About 90% of maximal F can be achieved at $Dn{\approx}2$. Increasing the solubility of a drug results in better oral absorption through increasing Dn and decreasing the solubility of a drug results in better oral absorption through increasing Dn and decreasing Do. The fractions dose absorbed of digoxin, griseofulvin, and benoxaprofen agree with predicted F values sorbed by reducing particle size, while absorption of drugs with high Do and low Dn is limited by solubility and requires higher solubility to enhance the fraction dose absorbed in addition to micronization. Solubility at the physiological pH should be used for the estimation of the fraction dose absorbed.