• YAKHAK HOEJI
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• v.40 no.5
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• pp.522-531
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• 1996

5-fluorouracil(5-FU) derivatives synthesized with four N-acyloxycarbonyl group such as 1-(N-t-butyloxycarbonyl)glycyloxymethyl-5-FU(BGFU), 1-(N-t-butyloxycarbonyl)leucyloxymethy l-5-FU(BLFU), 1-(N-t-carbobenzyloxymethyl)glycyoxymethyl-5-FU(CGFU) and 1-(N-t-carbobenzyloxymethyl)leucyloxymethyl-5-FU(CLFU) were entrapped into liposomes with different lipid compositions. The entrapment efficiency and release rate of drugs from each liposomes were evaluated. The particle size of liposomes, cytotoxicity and stability of drug-entrapped in liposomes were evaluated. The entrapment efficiency in 5-FU derivatives liposomes was dependent on the lipophilicity of N-acyloxymethyl derivatives. The drug entrapment efficiency also increased on the content of lipid increased up to 200mcmol of lipid per milliliter of liposomal solution. However, inclusion of additives such as cholesterol, dicetylphosphate and stearylamine decreased the entrapment efficiency. The mean particle size and size distribution were varied with lipid compositions and lipophilicity of prodrugs. The release rates of drugs from liposomes were not affected by additives, but those of BGFU and CGFU entrapped in liposomes with cholesterol decreased. Cytotoxicity of BLFU and CLFU entrapped in liposomes decreased by 3~5 fold compared with those of free two prodrugs. Liposome-entrapped 5-FU prodrugs were more stable either at pH 7.4 or in human plasma. Especially, 5-FU prodrugs entrapped in liposome with dipalmitoylphosphatidylcholine(DMPC) was the most stable in human plasma. Compared with free BLFU, BLFU entrapped in DMPC liposome showed a superior antitumor activity at all doses used. In contrast, CLFU entapped in liposomes were more toxic than free prodrug.

• YAKHAK HOEJI
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• v.40 no.5
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• pp.532-538
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• 1996

In cancer chemotherapy, it is necessary to control the phamacokinetic behavior of an antitumor drug for effective treatment. Therefore, two 5-fluorouracil derivatives synthesize d with N-a-cyloxycarbonyl derivatives {1-(N-t-butyloxycarbonyl)leucyloxymethyl-5-FU(BLFU) and 1-(N-t-carbobenzyloxymethyl)leucyloxymethyl-5-FU(CLFU)}. prodrugs of 5-fluorouracil, antitumor agent, were loaded into liposome of different lipid compositions. After liposomal drugs were injected intramuscularly, their pharmacokinetics and tissue distribution were assessed. The $AUC_{0{\to}{\infty}$ values were 1.29, 72.50, 85.57, 66.40 and 103.60${\mu}$g.hr/ml for 5-FU, BLFU, CLFU, BLFU- and CLFU-loaded liposome, respectively. 5-FU was distributed to spleen and liver with a maximal concentration after 1 hr and eliminated after 24 hr. But both prodrugs and dimyristoylphosphatidylcholine liposome entrapped prodrugs were distributed to spleen and liver at a lower concentration but maintained for a long time with a relatively high concentration in lung. Especially, liposome-entrapped CLFU was distributed to lung with a maximal concentration after 1 hr and redistributed to spleen increasingly, while the concentration of liposome-entrapped BLFU in lung reached a maximal level after 12 hr.

• YAKHAK HOEJI
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• v.40 no.3
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• pp.279-292
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• 1996

To assess their stability as a prodrug of 5-fluorouracil (5-FU), four N-acyloxycarbonyl derivatives (1-(N-tert-butyloxycarbonyl)glycyloxymethyl-5-FU :BGFU, 1-(N-tert-butyloxycar bonyl)-leucyloxymethyl-5-FU:BLFU, 1-(N-tert-carbobenzyloxymethyl) glycyloxymethyl-5-FU:CGFU and 1-(N-tert-carbobenzlyoxymethyl)leucyloxymethyl-5-FU:CLFU) possessing differently protected amino acids, and two acetic acid derivatives (5FU-1-acetylpentane:FUAP and 5-FU-1-acetylhexane:FUAH) were synthesized and their physicochemical properties, hydrolysis kinetics, acute toxicity and antitumor activity were evaluated. The lipid-water partition coefficients of six 5-FU prodrugs were higher than that of 5-FU and their aqueous solubilities were in the following rank order; BGFU>FUAP>CGFU>BLFU>CLFU${\simeq}$FUAH. The hydrolysis of N-acyloxycarboyl derivatives, greater at higher pH, was enhanced in presence of liver homogenate or human plasma. Meanwhile, acetic acid ester derivatives, very stable, were hydrolyzed by liver homogenate. Absorption rate constants were 0.181, 0.121, 0.111, 0.168, 0.168, 0.116 and 0.125 $hr^{-1}$ for 5-FU, BGFU, BLFU, CGFU, CLFU, FUAP and FUAH, respectively. The cytotoxicity of N-acyloxycarbonyl derivatives was 4 to 5 times lower than that of 5-FU, but that of acetic acid ester derivatives was negligeble. The $LD_{50}$ values were 204, 325.97 (133.59, amount as 5-FU), 708.16 (262.13), 663.50 (211.77), 382.33 (192.54) and 272.33 (130.09) mg/kg for 5-FU, BGFU, CGFU, CLFU, FUAP and FUAH, respectively. While N-acyloxycarbonyl derivatives showed enhanced antitumor activity and therapeutic ratio (3.30, 3.06, 4.19, 3.11 and 1.81 for BGFU, BLFU, CGFU, CLFU and 5-FU, respectively), FUAH and FUAP showed a smaller therapeutic ratio (0.79 and 0.83).