2',3'-二脱氢-2',3'-二脱氧-2-氨基-6-环丙胺基嘌呤核糖核苷在大鼠体内的药物代谢动力学和生物利用度

2',3'-二脱氢-2',3'-二脱氧-2-氨基-6-环丙胺基嘌呤核糖核苷在大鼠体内的药物代谢动力学和生物利用度

刘薏, 杨振军^*, BOUDINOTF.Douglas, CHU Chung Kuang, 张礼和

1.北京大学药学院, 北京 100083;
2.北京信诺康达医药信息技术有限公司, 北京 100083;
3.Collegeof Pharmacy,The University of Georgia, Athens, Georgia 30602-2352, USA

收稿日期:2003-07-15 修回日期:2004-02-10 出版日期:2004-03-15 发布日期:2004-03-15
通讯作者: 杨振军*

Pharmacokinetics and Bioavailability of 2-Amino-6-Cyclopropylamino-9-(2,3-Dideoxy-β-D-glyceropent-2-enofuranosyl) Purine (Cyclo-D4G) in Rats

LIU Yi, YANG Zhen-jun^*, BOUDINOT F.Douglas, CHU Chung Kuang, ZHANG Li-he

1. School of Pharmaceutical Sciences, Peking University, Beijing 100083, China;
2. Beijing SinopmMedical Information Co. Ltd., Beijing 100083, China;
3. College of Pharmacy,The University of Georgia,Athens, Georgia 30602-2352, USA

Received:2003-07-15 Revised:2004-02-10 Online:2004-03-15 Published:2004-03-15
Contact: YANG Zhen-jun*

摘要/Abstract

摘要： 目的研究2', 3'-二脱氢-2', 3'-二脱氧-2-氨基-6-环丙胺基嘌呤核糖核苷(Cyclo-D4G, D4G前药)在大鼠体内经静注和口服的药物代谢动力学特征. 方法采用高效液相色谱法测定Cyclo-D4G在大鼠血浆和尿液中的浓度.结果静注后, 血浆中Cyclo-D4G的消除半衰期是0.78±0.14 h (x±s), 总清除率为0.90±0.21 L·h^-1·kg^-1, 原药在尿中的排泄分数约为20%, 稳态分布体积为0.91±0.07 L·kg^-1.口服后, 血浆中Cyclo-D4G的消除半衰期为0.83±0.13 h (x±s), 总清除率为3.81±2.03 L·h^-1·kg^-1, 原药在尿中的排泄分数约为9%.Cyclo-D4G的口服生物利用度为26.9%. 结论 Cyclo-D4G表现出较好的药代动力学性质和较低的毒性,可以做进一步的动物试验和临床试验.

关键词: 药物代谢动力学, 生物利用度, 高效液相色谱分析, D4G前药

Abstract: Aim To characterize the pharmacokinetics of 2-amino-6-cyclopropylamino-9-(2,3-dideoxy-β-D-glyceropent-2-enofuranosyl) purine (Cyclo-D4G) following intravenous administration and oral administration to rats. Methods The concentrations of Cyclo-D4G in rat (Sprague-Dawley male rats) plasma and urine were analyzed by high performance liquid chromatography (HPLC). Results Following intravenous administration to rats, concentrations of Cyclo-D4G in plasma declined with a terminal phase half-life of 0.78±0.14 h (x±s).Total clearance was 0.90±0.21 L·h^-1·kg^-1. Renal excretion of unchanged Cyclo-D4G accounted for approximately 20% of total clearance.Steady state volume of distribution was 0.91±0.07 L·kg^-1. After oral administration to rats, concentrations of Cyclo-D4G in plasma declined with a terminal phase half-life of 0.83±0.13 h (x±s).Total clearance was 3.81±2.03 L·h^-1·kg^-1. Renal excretion of unchanged Cyclo-D4G accounted for approximately 9% of total clearance.Oral bioavailability of Cyclo-D4G in rat was 26.9%. Conclusion The favorable pharmacokinetic profiles and lower toxicity provide support for further development of Cyclo-D4G clinical trials.

Key words: pharmacokinetics, pharmacokinetics, bioavailability, bioavailability, HPLC analysi s, HPLC analysi s, D4G prodrug, D4G prodrug

中图分类号:

R969.1

R917.797

Supporting: ^*Corresponding author. Tel.: 010-82801570; fax: 010-82802503

刘薏, 杨振军^*, BOUDINOTF.Douglas, CHU Chung Kuang, 张礼和. 2',3'-二脱氢-2',3'-二脱氧-2-氨基-6-环丙胺基嘌呤核糖核苷在大鼠体内的药物代谢动力学和生物利用度[J]. .

LIU Yi, YANG Zhen-jun^*, BOUDINOT F.Douglas, CHU Chung Kuang, ZHANG Li-he . Pharmacokinetics and Bioavailability of 2-Amino-6-Cyclopropylamino-9-(2,3-Dideoxy-β-D-glyceropent-2-enofuranosyl) Purine (Cyclo-D4G) in Rats[J]. .

参考文献

[1] Faletto MB, Miller WH, Garvey EP, et al. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89 [J]. Antimicrob Agents Chemother, 1997, 41: 1099-1107.
[2] Dobkin J F. Two new agents for HIV: Kaletra and trizivir [J]. Infect Med, 2000, 17: 777.
[3] Trizivir-Abacavir sulfate/lamivudine/zidovudine tablets-Glaxo Wellcome-Fixed-dose combination of 3 nucleoside analogs for twice-daily Tx of HIV [J]. Formulary, 2001, 36: 13.
[4] Ray AS, Yang ZJ, Chu CK, et al. A novel use of a guanosine prodrug approach to covert 2’, 3’-didydro-2’, 3’-dideoxyguanosine into a viable antiviral agent [J]. Antimicrob Agents Chemothe, 2002, 46: 887-891.
[5] Liu Y, Yang ZJ, Boudinot FD, et al. Determination of 2-amino-6-cyclopropylamino-9-(2,3-dideoxy-β-D-glyceropent-2-enofuranosyl) purine in rat plasma, urine and liver homogenates by high performance liquid chromatography [J]. J Chin Pharm Sci, 2003, 12: 93-97.
[6] Gerlowski LE, Jain PK. Physiologically based pharmacokinetic modeling: principles and application [J]. J Pharm Sci,1983, 72: 1103-1105.
[7] Furman PA, Barry DW. Spectrum of antiviral activity and mechanism of action of zidovudine an overview [J]. Am J Med, 1988, 85 (Suppl. 2A): 176-181.
[8] Mitsuya HR, Yarchoan SK, Broder S. Targeted therapy of human immunodeficiency virus-related disease [J]. FASEB J, 1991, 5: 2369-2381.
[9] Parker WB, White EL, Shaddix SC, et al. Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase and human DNA polymerases α, β, γ by the 5’-triphosphates of carbovir, 3’-azido-3’-deoxythymidine, 2’,3’-dideoxyguanosine, and 3’-deoxythymidine [J]. J Biol Chem, 1991, 266: 1754-1762.
[10] Faletto MB, Miller WH, Garvey EP, et al. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89 [J]. Antimicrob Agents Chemother, 1997, 41: 1099-1107.
[11] Daluge SM, Good SS, Faletto MB, et al. 1592U89, a noval carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity [J]. Antimicrob Agents Chemother, 1997, 41: 1082-1093.
[12] Wientjes MG, Mukherji E, Au JL-S. Nonlinear disposition of intravenous 2’, 3’-dideoxyinosine in rats [J]. Pharm Res,1992, 9: 1070-1075.
[13] Unadkat JD, Wang JP, Pulham D, et al. Dose-ranging pharmacokinetics of zidovudine (azidothymidine) in the rat [J]. Pharm Res, 1989, 6: 734-736.
[14] Boudinot FD, Smith SG, Funderburg ED, et al. Pharmacokinetics of 3’-fluoro-3’-deoxythymidine and 3’-deoxy-2’,3’-didehydrothymidine in rats [J]. Antimicrob Agents Chemother,1991, 35: 747-749.
[15] Ibrahim SS, Boudinot FD, Pharmacokinetics of 2’, 3’-dideoxycytidine in rats [J]. J Pharm Pharmacol, 1989, 41: 829-834.
[16] Patel BA, Chu CK, Boudinot FD. Pharmacokinetics and saturable renal tubular secretion of zidovudine in rats [J]. J Pharm Sci, 1989, 78: 530-534.