AimTo characterize the pharmacokinetics of 2 -amino-6-cyclopropylamino-9-(2,3-dideoxy-β-D-glyceropent-2-enofuran osyl) purine (Cyclo-D4G) following intravenous administration and oral administ ration to rats. Methods...AimTo characterize the pharmacokinetics of 2 -amino-6-cyclopropylamino-9-(2,3-dideoxy-β-D-glyceropent-2-enofuran osyl) purine (Cyclo-D4G) following intravenous administration and oral administ ration to rats. MethodsThe concentrations of Cyclo-D4G in rat (Sprague-Dawley male rats) plasma and urine were analyzed by high performance liquid chromatography (HPLC). ResultsFollowing intravenous adm inistration to rats, concentrations of Cyclo-D4G in plasma declined with a term inal phase half-life of 0 78±0 14 h (±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 distr ibution was 0 91±0 07 L·kg -1 . After oral administration to rats, conce ntrations of Cyclo-D4G in plasma declined with a terminal phase half-life of 0 83±0 13 h (±s). Total clearance was 3 81±2 03 L·h -1 ·kg -1 . Renal excretion of unchanged Cyclo-D4G accounted for approximat ely 9% of total clearance. Oral bioavailability of Cyclo-D4G in rat was 26 9%. ConclusionThe favorable pharmacokinetic profiles and lower to xicity provide support for further development of Cyclo-D4G clinical trials.展开更多
Aim To develop a simple and specific high-performance liquid chromatographic(HPLC) method, suitable for the pharmacokinetic studies in vivo, to determine the concentrations of2-amino-6-cyclopropylamino-9-(2,3-dideoxy-...Aim To develop a simple and specific high-performance liquid chromatographic(HPLC) method, suitable for the pharmacokinetic studies in vivo, to determine the concentrations of2-amino-6-cyclopropylamino-9-(2,3-dideoxy-β-D-glyceropent-2-enofuranosyl)purine (Cyclo-D4G, IMGprodrug) in rat plasma, urine and liver homogenates. Methods Chromatography was performed with C-18Hypersil ODS column and a mobile phase of 7% (v/v) acetonitrile in phosphate buffer, pH 7.40, withUV detection at 283 nm. Results The average extraction recovery of Cyclo-D4G in rat plasma and urinewas 100.1% over its linear range of 0.5 - 80 μg·mL^(-1). The accuracy of the assay was 99.4% .The intra-and inter-day RSDs were less than 9.0% . Conclusion The analytical method was found to beapplicable, reliable and suitable for pharmacokinetic studies.展开更多
In search of potential 2＇,3＇-dideoxyguanosine （ddG） and 2＇,3＇-didehydro-2＇,3＇-dideoxyguanosine （D4G） prodrugs, a series of 6-modified ddG, D4G analogs were synthesized and evaluated for their anti-HIV activi...In search of potential 2＇,3＇-dideoxyguanosine （ddG） and 2＇,3＇-didehydro-2＇,3＇-dideoxyguanosine （D4G） prodrugs, a series of 6-modified ddG, D4G analogs were synthesized and evaluated for their anti-HIV activities and cyto- toxities in cell-based assays. All analogs showed low cytotoxieities and some of them displayed benign anti-HIV activities. The active triphosphate forms in vivo, ddGTP and D4TTP, were also synthesized by a novel and facile ＂one-pot＂ method. The recognition of ddGTP and D4TTP by Taq, Therminater DNA polymerase and HIV reverse transcriptase （RT） incorporated in DNA/RNA strands were investigated by a non-radioactivity method and Km were determined.展开更多
文摘AimTo characterize the pharmacokinetics of 2 -amino-6-cyclopropylamino-9-(2,3-dideoxy-β-D-glyceropent-2-enofuran osyl) purine (Cyclo-D4G) following intravenous administration and oral administ ration to rats. MethodsThe concentrations of Cyclo-D4G in rat (Sprague-Dawley male rats) plasma and urine were analyzed by high performance liquid chromatography (HPLC). ResultsFollowing intravenous adm inistration to rats, concentrations of Cyclo-D4G in plasma declined with a term inal phase half-life of 0 78±0 14 h (±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 distr ibution was 0 91±0 07 L·kg -1 . After oral administration to rats, conce ntrations of Cyclo-D4G in plasma declined with a terminal phase half-life of 0 83±0 13 h (±s). Total clearance was 3 81±2 03 L·h -1 ·kg -1 . Renal excretion of unchanged Cyclo-D4G accounted for approximat ely 9% of total clearance. Oral bioavailability of Cyclo-D4G in rat was 26 9%. ConclusionThe favorable pharmacokinetic profiles and lower to xicity provide support for further development of Cyclo-D4G clinical trials.
文摘Aim To develop a simple and specific high-performance liquid chromatographic(HPLC) method, suitable for the pharmacokinetic studies in vivo, to determine the concentrations of2-amino-6-cyclopropylamino-9-(2,3-dideoxy-β-D-glyceropent-2-enofuranosyl)purine (Cyclo-D4G, IMGprodrug) in rat plasma, urine and liver homogenates. Methods Chromatography was performed with C-18Hypersil ODS column and a mobile phase of 7% (v/v) acetonitrile in phosphate buffer, pH 7.40, withUV detection at 283 nm. Results The average extraction recovery of Cyclo-D4G in rat plasma and urinewas 100.1% over its linear range of 0.5 - 80 μg·mL^(-1). The accuracy of the assay was 99.4% .The intra-and inter-day RSDs were less than 9.0% . Conclusion The analytical method was found to beapplicable, reliable and suitable for pharmacokinetic studies.
基金The research was supported by the fund of the National Natural Science Foundation of China，the Ministry of Science and Technology of China (No.2008ZX10303).Anti-HIV activity evaluation in pseudotyped HIV system was performed by Institute of Materia Medica,Chinese Academy of Medical Science and Peking Union Medical College.Anti-HIV activity evaluation in HIV-1/MT2 cells was performed by HD
文摘In search of potential 2＇,3＇-dideoxyguanosine （ddG） and 2＇,3＇-didehydro-2＇,3＇-dideoxyguanosine （D4G） prodrugs, a series of 6-modified ddG, D4G analogs were synthesized and evaluated for their anti-HIV activities and cyto- toxities in cell-based assays. All analogs showed low cytotoxieities and some of them displayed benign anti-HIV activities. The active triphosphate forms in vivo, ddGTP and D4TTP, were also synthesized by a novel and facile ＂one-pot＂ method. The recognition of ddGTP and D4TTP by Taq, Therminater DNA polymerase and HIV reverse transcriptase （RT） incorporated in DNA/RNA strands were investigated by a non-radioactivity method and Km were determined.
