Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats.
The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C max) were 0.42, 1.50 and 2.55 μg/mL, the area under the curve (AUC0-t) were 0.89, 2.27 and 3.96 µg/h mL and the plasma half-life (t 1/2) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96-99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.
Department of Pharmacology, School of Basic Medical Science, Beijing (Peking) University, No.38, Xue-Yuan Road, Beijing, 100191, People's Republic of China.
Ying-Yuan
YY
Lu
Department of Chemical Biology, School of Pharmaceutical Sciences, Beijing (Peking) University, Beijing, 100191, People's Republic of China.
Xiao-Wei
XW
Wang
Department of Pharmacology, School of Basic Medical Science, Beijing (Peking) University, No.38, Xue-Yuan Road, Beijing, 100191, People's Republic of China.
Xin
X
Wang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Beijing (Peking) University, Beijing, 100191, People's Republic of China.
Wen-Bing
WB
Dai
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Beijing (Peking) University, Beijing, 100191, People's Republic of China.
Qiang
Q
Zhang
Department of Pharmacology, School of Basic Medical Science, Beijing (Peking) University, No.38, Xue-Yuan Road, Beijing, 100191, People's Republic of China.
Pu
P
Li
Department of Pharmacology, School of Basic Medical Science, Beijing (Peking) University, No.38, Xue-Yuan Road, Beijing, 100191, People's Republic of China.
Ya-Qing
YQ
Lou
Department of Drug Metabolism & Pharmacokinetics, Biogen, MA, USA.
Chuang
C
Lu
Department of Chemical Biology, School of Pharmaceutical Sciences, Beijing (Peking) University, Beijing, 100191, People's Republic of China.
Jun-Yi
JY
Liu
Department of Pharmacology, School of Basic Medical Science, Beijing (Peking) University, No.38, Xue-Yuan Road, Beijing, 100191, People's Republic of China. ZhangGL168@bjmu.edu.cn.
Guo-Liang
GL
Zhang
D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000378:metabolism* / Q000652:urine; D004285:Dogs; D005260:Female; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D065667:Renal Elimination / Q000187:drug effects / Q000502:physiology; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000378:metabolism* / Q000652:urine; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors
6-Benzyl-1-benzyloxymethyl-5-iodouracil (W-1); Disposition; Excretion; Plasma protein binding; Rat; Tissue distribution