• Journal of Pharmaceutical Investigation
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• v.18 no.3
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• pp.139-144
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• 1988

Piperacillin phthalidyl ester was synthesized by reacting piperacillin with triethylamine and bromophthalide in acetone and its chemical structure was determined by UV, IR, and PMR. The partition coefficient of the ester was increased and the ester was more lipophilic and less water soluble than piperacillin. The ester did not show the antimicrobial activity against Bacillus subtilis ATCC 6633 in vitro, but when hydrolyzed, the parent drug of ester, piperacillin, revealed antimicrobial activity in vivo. After a single oral dose of both piperacillin and the ester to rabbits, the serum piperacillin concentration was measured by bioassay. The ester exhibited improved pharmatokinetic characteristics: $T_{max}\;of\;2hr,\;C_{max}\;of\;4.26{\mu}g{\cdot}ml^{-1},K_{el}\;of\;0.057hr^{-1},\;and\;total\;AUC\;of\;85.42{\mu}g{\cdot}hr{\cdot}ml^{-1}$. Piperacillin on the other hand, did not exhibit any gastro-intestinal absorption.

• Proceedings of the PSK Conference
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• 2000.04a
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• pp.164.2-165
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• 2000

• Proceedings of the PSK Conference
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• 2001.10a
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• pp.296.2-297
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• 2001

• Journal of Pharmaceutical Investigation
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• v.19 no.1
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• pp.21-27
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• 1989

Kinetic and thermodynamic aspects of the interface transfer of cefoperazone and its pivaloyloxymethyl ester were studied in a two-phase system composed of aqueous buffers and n-octanol by using the absolute reaction rate theory. In terms of the net thermodynamic parameters for the process, ${\Delta}S$ increased and ${\Delta}F$ decreased as the lipophilicity increased. With the increased ratio of forward $(k_f)$ to backward rate constants $(k_b)$, the ester was more lipophilic than cefoperazone, but the aqueous solubility was reduced.

• Korean Journal of Clinical Pharmacy
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• v.3 no.1
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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.

• Archives of Pharmacal Research
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• v.26 no.4
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• pp.258-263
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• 2003

Colon-specific delivery of glucocorticoids is highly desirable for the efficient treatment of inflammatory bowel disease. We synthesized prednisolone 21-sulfate sodium (PDS) as a colon-specific prodrug of prednisolone (PD) and investigated its properties using rats as test animals. We expected that introduction of sulfate ester as a sodium salt might increase the hydrophilicity and restrict the absorption in the GI tract. If PDS is stable and nonabsorbable in the upper intestine, it will be delivered to the colon as an intact form, where it hydrolyze by the sulfatase to release PD. Compared with PD, the solubility of PDS increased and the apparent partition coefficient decreased greatly. PDS was stable on incubation with pH 1.2 and 6.8 buffer solutions and with the contents of the stomach and small intestine. On incubation with the cecal contents, PDS decreased to 9.6％ of the dose in 10 h producing PD. The amount of PD increased to give a maximum 54％ of the dose and decreased. As a control, when PD was incubated with the cecal contents, it decreased to 29％ of the dose in 8 h, which implied that reduction of PD proceeded under such conditions. These results suggested that hydrolysis of PDS took place to produce and accumulate PD, which decreased by reduction as the incubation period extended. Our results suggested that PDS can be a promising colon-specific prodrug of PD, and sulfate ester group might serve as a potential colon-specific promoiety, especially for the drugs which are resistant to reduction in the colon.

• Journal of Pharmaceutical Investigation
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• v.34 no.2
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• pp.107-114
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• 2004

External lyogels containing prostaglandin $E_1$ ethyl ester $(PGE_1-EE)$, a prodrug of prostaglandin $E_1\;(PGE_1)$ as a therapeutic agent for erectile dysfunction, were formulated to overcome the aqueous instability and enhance the percutaneous absorption. Lyogels of $PGE_1-EE$ were prepared with ethanol (EtOH)/proplyene glycol (PG) cosolvent system as a vehicle, cineol as an enhancer, and hydroxypropylcellusose as a gelling agent. In vitro percutaneous absorption studies were performed to determine the rate of $PGE_1$ absorption through rat or hairless mouse skin. The permeability of $PGE_1-EE$ lyogel with enhancer was 16-fold greater than that of lyogel without enhancer. Cosolvent produced 9-fold increase in percutaneous absorption. Pharmacodynamic effects of lyogels were evaluated in mature male cats in terms of intracavernosal pressure (ICP). Lyogels containing 0.1 % of $PGE_1-EE$ showed higher ICP compared to intraurethral preparation of $PGE_1$ (1 %) and enhancer-free control lyogel. The shelf-life $(t_{10%})$ of lyogel at refrigerated condition $(4^{\circ}C)$ was calculated as 928 days, which is 4.2 times longer than that of control hydrogel. As a result, $PGE_1-EE$ was formulated successfully to a lyogel system with a selective enhancer and cosolvent system for the topical delivery of $PGE_1$.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.418.3-419
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• 2002

Enalapril. a prodrug. is the ethyl ester of a long-acting angiotensin converting enzyme inhibitor. enalaprilat. Because enalapril does not contain any appreciable chromophore. detection of the drug in a complex matrix (e.g.. biological fluids) has been problematic with conventional detection systems in high-performance liquid chromatography (HPLC). As a result. determination of enalaprillevel in blood samples has been typically carried out using HPLC-MS/MS in the literature. (omitted)

• Journal of Microbiology and Biotechnology
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• v.27 no.11
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• pp.1916-1924
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• 2017

In this study, we synthesized a glycosylated derivative of caffeic acid phenethyl ester (CAPE) using the amylosucrase from Deinococcus geothermalis with sucrose as a substrate and examined its solubility, chemical stability, and anti-inflammatory activity. Nuclear magnetic resonance spectroscopy showed that the resulting glycosylated CAPE (G-CAPE) was the new compound caffeic acid phenethyl ester-4-O-${\alpha}-{\small{D}}$-glucopyranoside. G-CAPE was 770 times more soluble than CAPE and highly stable in Dulbecco's modified Eagle's medium and buffered solutions, as estimated by its half-life. The glycosylation of CAPE did not significantly affect its anti-inflammatory activity, which was assessed by examining lipopolysaccharide-induced nitric oxide production and using a nuclear factor erythroid 2-related factor 2 reporter assay. Furthermore, a cellular uptake experiment using high-performance liquid chromatography analysis of the cell-free extracts of RAW 264.7 cells demonstrated that G-CAPE was gradually converted to CAPE within the cells. These results demonstrate that the glycosylation of CAPE increases its bioavailability by helping to protect this vital molecule from chemical or enzymatic oxidation, indicating that G-CAPE is a promising candidate for prodrug therapy.

• Journal of Pharmaceutical Investigation
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• v.31 no.2
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• pp.95-100
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• 2001

Various alkyl ester prodrugs of diclofenac were synthesized in order to investigate the relationship between their skin permeation characteristics and physicochemical properties. Solubility in various vehicles was measured at room temperature. 1-Octanol/water partition coefficients (Log P) and capacity factors (k') were measured to determine the lipophilicity of the prodrugs. Stability of prodrugs in the skin extract and homogenate was also investigated before conducting the skin permeation studies. Increases in the Log P and capacity factor values were observed when alkyl esters of diclofenac were prepared. Since the aqueous solubility of the prodrugs was not high enough, they were saturated in propylene glycol (PG) for skin permeation studies. Prodrugs were rapidly metabolized to diclofenac, both in skin homogenate and in dermal extract of skin. The skin permeation rate of alkyl ester prodrugs was significantly higher than diclofenac with shorter lag time. Moreover, a parabolic relationship was observed between the permeation rate and the log P values of prodrugs, and the maximum flux was achieved at a log P value of around 4.0.