• YAKHAK HOEJI
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• v.24 no.1
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• pp.11-14
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• 1980

In order to increase the gastro-intestinal absorption of cephalexin, a new cephalexin phthalidyl ester was synthetized. Comparative studies of cephalexin phthalidyl ester in the gastro-intestinal absorption were conducted after oral administration in rabbits. The amounts of cephalexin in plasma were determined by a fluorometric method. Cephalexin phthalexin phthalidyl ester could not be identified in plasma, but only cephalexin was found by TLC method. In comparison with cephalexin, cephalexin phthalidyl ester produced much higher plasma levels of cephalexin than did cephalexin itself after its oral administration in rabbits.

• Journal of Pharmaceutical Investigation
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• v.23 no.2
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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.

• Journal of Pharmaceutical Investigation
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• v.25 no.4
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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.

• YAKHAK HOEJI
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• v.42 no.1
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• pp.31-38
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• 1998

Dextran-5-(4-ethoxycarbonylphenylazo)salicylic acid ester(Dextran-5-ESA) was synthesized as a potential colon-specific prodrug of 5-aminosalicylic acid (5-ASA). No free 5-(4-eth oxycarbonylphenylazo) salicylic acid (5-ESA) was detected when the chemical stability of dextran-5-ESA was tested at pH 1.2, or pH 6.8 bath solution, Effects of the degree of substitution (DS) and molecular weight of dextran on the depolymerization by dextranase was investigated. Depolymerization(%) decreased with increasing DS, and was not affected by M.W. of dextran. The extent of prodrug conversion after incubation in the contents of various G.I. Tract segments of rats was evaluated. 5-ASA was released in the cecal contents, but not in the contents of proximal small intestine (PSI) or distal small intestine (DSI). No significant prodrug conversion was observed in the cecal contents of rats pretreated with kanamycin sulfate, which indicated that microbial enzymes were responsible for the cleavage of the prodrug.

• Journal of Pharmaceutical Investigation
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• v.18 no.4
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• pp.197-201
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• 1988

Pivaloyloxymethyl ester of cefoperazone was synthesized by treating sodium cefoperazone with chloromethyl pivalate and its chemical structure was determined by spectroscopic trials. The pharmaceutical properties of the ester were investigated to assess its potential as a prodrug of cefo perazone. Cefoperazone pivaloyloxymethyl ester was microbiologically inactive itself in vitro, but hydrolyzed into the parent drug in vivo. After a single oral dose of each drug to rabbits, serum concentrations of cefoperazone were determined by high performance liquid chromatographic assay. The ester showed higher and more sustained blood level than cefoperazone. Therefore, the total area under the serum concentration-time curve of the derivative was 16.8 times larger than that of the parent drug.

• Journal of Pharmaceutical Investigation
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• v.22 no.2
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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.

• Journal of Pharmaceutical Investigation
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• v.24 no.4
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• pp.265-271
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• 1994

Cefazolin ethoxycarbonylethyl ester (CFZ-ET) was synthesized to improve oral absorption and bioavailability of the parent drug by esterification of sodium cefazolin (CFZ-Na). The successful synthesis of CFZ-ET was identified with analysis of UV spectra, FT-lR spectra and NMR spectra. Partition coefficient studies showed that CFZ-ET was more lipophilic than CFZ-Na and the ester was hydrolyzed into the parent drug in vivo. Although CFZ-ET did not have antimicrobial activity in vitro, the plasma taken after the oral administration of CFZ-ET had antimicrobial activity. Based on above observations, CFZ-ET might be rapidly hydrolyzed to CFZ in the body. Therefore, it may be concluded that CFZ-ET could be a novel prodrug of CFZ which can improve the bioavailability of CFZ-Na.

• Korean Journal of Clinical Pharmacy
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• v.8 no.2
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• pp.133-138
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• 1998

Phthalimidyl ester of ceftezole (CFZ-PT) was synthesized as a prodrug by esterification of ceftezole (CFZ) with N-bromophthalimide. CFZ-PT was more lipophilic than CFZ when the lipophilicity was assessed by partition coefficients between n-octanol and water at various pH. The pharmacokinetic characteristic of CFZ-PT and CFZ preparations were compared following oral administrations of these compounds to rabbits. CFZ-PT is expected to be metabolized rapidly to CFZ in the body. The metabolism process appears to be hydrolysis of the ester to CFZ, the parent drug of CFZ-PT. In vivo metabolism of CFZ-PT to CFZ was confirmed in rabbit by HPLC analysis. CFZ concentration in the serum samples taken after oral administration of CFZ-PT(equivalent amount of CFZ) were released and higher than those of CFZ. Oral bioavailability of CFZ-PT was 1.9 fold higher than at of CFZ in rabbits because of enhanced lipophilicity and absorption. Finally, it was concluded that CFZ-PT appears useful as a prodrug of CFZ to improve the oral bioavailability of CFZ.

• Journal of Pharmaceutical Investigation
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• v.27 no.2
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• pp.125-131
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• 1997

Ethoxycarbonyloxyethyl ester of ceftezole (CFZ-ET) was synthesized as a prodrug by esterification of ceftezole (CFZ) with ethoxycarbonyloxyethyl chloride and was confirmed by spectroscopic analyses. CFZ-ET was more lipophillic than CFZ as assessed by n-octanol and water partition coefficients at various pH. CFZ-ET itself did not show any microbiological activity in vitro, but showed substaintial microbiological activity after oral administration of CFZ-ET, indicating that CFZ-ET is converted to microbiologically active metabolite, probably CFZ, in the body. When CFZ-ET was incubated in blood, liver and intestine homogenates of rabbits, liver homogenate showed the fastest conversion of CFZ-ET. CFZ-ET appears rapidly metabolized in the liver when given orally due to the hydrolysis of the ester to CFZ, the parent drug of CFZ-ET. In vivo metabolism of CFZ-ET to CFZ was confirmed in rabbit by HPLC analysis. CFZ-ET were higher than those in the serum samples taken after oral administration of equivalent amount of CFZ. Oral bioavailability of CFZ-ET was 1.5-fold higher than that of CFZ in rabbits because of enhanced lipophilicity and absorption. Based on these findings, CFZ-ET appears useful as a prodrug of CFZ to improve the oral bioavailability of CFZ.

• YAKHAK HOEJI
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• v.47 no.5
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• pp.331-338
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• 2003

A butyrolactone ester of cefazolin (CFZ-BTL) was synthesized by the esterification of cefazolin (CFZ) with $\alpha$-bromo-${\gamma}$-butyrolactone. The synthesis was confirmed by the spectroscopic analysis. The CFZ-BTL was more lipophilic than the CFZ when assessed by n-octanol/water partition coefficients at various pH. The CFZ-BTL itself did not show any antimicrobial activity in vitro, but after oral administration of CFZ-BTL to rabbits, exerted significant anti-microbial activity in serum samples when measured by the inhibion zone method in nutrient agar plates, due to conversion of CFZ-BTL to an active metabolite, probably CFZ, in the body. The CFZ-BTL was also converted into CFZ as confirmed by in vitro incubation study, with tissue homogenates (liver, blood and intestine) of rabbits. The liver showed the fastest conversion rate, probably via the hydrolysis mechanism. In vivo metabolism of CFZ-BTL to CFZ was also confirmed in vivo serum samples by HPLC. The oral bioavailability of CFZ-BTL in rabbits was 1.6-fold increased when compared to CFZ, resulting from followed by enhanced lipophilicity increased passive absorption in the intestine.