Abstract
Aim:
To study the pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes (5-Fu-GCL) in mice.
Methods:
The concentration of 5-fluorouracil (5-Fu) in serum was detected by high performance liquid chromatography after 5-Fu-GCL (80, 40, 20 mg/kg) and free 5-Fu (40 mg/kg) were injected intravenously into mice. The tissue distribution of 5-Fu-GCL (40 mg/kg) and free 5-Fu (40 mg/kg) was investigated, and concentration-time profile of the two preparations in the liver were studied. Data were analyzed by 3p97 program.
Results:
Serum concentration-time curves of 5-Fu-GCL and free 5-Fu conformed to one compartment model of first order absorption. 5-Fu-GCL at 80, 40, and 20 mg/kg had T1/2Ke of 25.8±4.2, 27.3±4.4, and 28.2±5.6 min; C0 of 24.9±4.9, 17.7±3.6, and 11.5±2.7 mg/L; and AUC of 990.0±45.2, 622.5±38.3, and 340.4±25.6 mg·min·L-1, respectively. In contrast free 5-Fu at 40 kg/mg had T1/2Ke of 15.8±2.2 min, C0 of 35.8±6.2 mg/L, AUC of 639.0±35.9 mg·min·L-1. The tissue distribution of 5-Fu-GCL in the liver and immune organs was significantly increased, while in heart and kidney it was remarkably decreased. The AUC of 5-Fu-GCL in the liver was 3 times higher than that of free 5-Fu.
Conclusion:
The pharmacokinetics and tissue distribution of 5-Fu-GCL appears to be linear-related and dose-dependent, and exhibits sustained-release and hepatic target characteristics.
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Cao S, Rustum YM . Synergistic antitumor activity of irinotecan in combination with 5-fluorouracil in rats bearing advanced colorectal cancer: role of drug sequence and dose. Cancer Res 2000; 60: 3717–21.
Di Paolo A, Danesi R, Falcone A, Cionini L, Vannozzi F, Masi G, et al. Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients. Ann Oncol 2001; 12: 1301–6.
Schlemmer HP, Becker M, Bachert P, Dietz A, Rudat V, Vanselow B, et al. Alterations of intratumoral pharmacokinetics of 5-fluorouracil in head and neck carcinoma during simultaneous radiochemotherapy. Cancer Res 1999; 59: 2363–9.
Fraile RJ, Baker LH, Buroker TR, Horwitz J, Vaitkevicius VK . Pharmacokinetics of 5-fluorouracil administered orally, by rapid intravenous and by slow infusion. Cancer Res 1980; 40: 2223–8.
Hagiwara A, Sakakura C, Shirasu M, Yamasaki J, Togawa T, Takahashi T, et al. Therapeutic effects of 5-fluorouracil microspheres on peritoneal carcinomatosis induced by Colon 26 or B-16 melanoma in mice. Anticancer Drugs 1998; 9: 287–9.
Jing M, Xi S, Chen R . The inhibitory effect of tissue plasminogen activator combined with 5-fluorouracil polyphase liposome on the scar formation in experimental filtration surgery. Chin J Ophthalmol 1997; 33: 376–80. Chinese.
Wang G, Tucker IG, Roberts MS . In vitro and in vivo evaluation in rabbits of a controlled release 5-fluorouracil subconjunctival implants base on poly (D, L-lactide-co-glycoside). J Control Release 1996; 13: 1059–64.
Umejima H, Kikuchi A, Kim NS, Uchida T, Goto S . Preparation and evaluation of Eudragit gels. VIII. Rectal absorption of 5-fluorouracil from Eudispert hv gels in rats. J Pharm Sci 1995; 84: 199–202.
Kuan HY, Smith DE, Ensminger WD, Knol JA, De Remer SJ, Yang Z, et al. Regional pharmacokinetics of 5-fluorouracil in dogs: role of the liver, gastrointestinal tract, and lungs. Cancer Res 1998; 58: 1688–94.
Zhao MZ, Zhao YK, Zhu LY, Xu G, Wang S, Mi JB, et al. Pharmacokinetics and tissue distribution of iv injection of polyphase liposomeencapsulated cisplatin (KM-1) in rats. Acta Pharmacol Sin 2003; 24: 89–92.
Jung M, Berger G, Pohlen U, Pauser S, Reszka R, Buhr HJ . Simultaneous determination of 5-fluorouracil and its active metabolites in serum and tissue by HPLC. J Chromatogr B 1997; 702: 193–203.
Joulia JM, Pinguet F, Grosse PY, Astre C, Bressolle F . Determination of 5-fluorouracil and its main metabolites in plasma by highperformance liquid chromatography: application to a pharmacokinetic study. J Chromatogr B 1997; 692: 427–35.
Gregoriadis G . Engineering liposomes for drug delivery: progress and problems. Trends Biotechnol 1995; 13: 527–37.
Nishikawa M, Hirabayashi H, Takakura Y, Hashida M . Design for cell-specific targeting of proteins utilizing sugar-recognition mechanism: effect of molecular weight of proteins on targeting efficiency. Pharm Res 1995; 12: 209–14.
Murahashi N, Ishihara H, Sasaki A, Sakagami M, Hamana H . Hepatic accumulation of glutamic acid branched neogalactosyllipid modified liposomes. Biol Pharm Bull 1997; 20: 259–66.
Tsuji H, Osaka S, Kiwada H . Targeting of liposomes surface-modified with glycyrrhizin to the liver. I. Preparation and biological disposition. Chem Pharm Bull 1991; 39: 1004–8.
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Project supported by Key Teacher Foundation of Ministry of Education of China (No 1869) and Young Teacher Foundation of Department of Education of Anhui Province (No 2000jg112).
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Jin, Y., Li, J., Rong, Lf. et al. Pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes in mice. Acta Pharmacol Sin 26, 250–256 (2005). https://doi.org/10.1111/j.1745-7254.2005.00530.x
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DOI: https://doi.org/10.1111/j.1745-7254.2005.00530.x
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