Pharmacokinetics and tissue distribution of (+/-)-3 '-azido-2 ',3 '-dideoxy-5 '-O-(2-bromomyristoyl)thymidine a prodrug of 3 '-azido-2 ',3 '-dideoxythymidine (AZT) in mice

The in-vivo biodistribution and pharmacokinetics in mice of 3'-azido-2',3'- dideoxythymidine (1, AZT), 2-bromomyristic acid (2) and their common prodru g, (+/-)-3'-azido-2',3' di de oxy-5'-O-(2-bromomyristoyl)thymidine (3) are reported. The objectives of the work were to enhance the anti-human immunod eficiency virus and anti-fungal effects of 1 and 2 by improving their deliv ery to the brain and liver. The pharmacokinetics of AZT (beta t 1/2 (elimination, or beta-phase, half-l ife) = 112.5 min; AUC (area under the plot of concentration against time) = 29.1 +/- 2.9 mu mol g(-1) min; CL (blood clearance) = 10.5 +/- 1.1 mL min( -1) kg(-1)) and its ester prodrug (3, beta t 1/2 = 428.5 min; AUC = 17.3 +/ - 4.7 mu mol g(-1) min; CL = 17.6 +/- 4.8 mL min(-1) kg(-1)) were compared after intravenous injection of equimolar doses (0.3 mmol kg(-1)) via the ta il vein of Balb/c mice (25-30 g). The prodrug was rapidly converted to AZT in-vivo, but plasma levels of AZT (peak concentration 0.17 mu mol g(-1)) an d AUC (12.3 mu mol min g(-1)) were lower than observed after AZT administra tion (peak concentration 0.36 mu mol g(-1); AUC 29.1 mu mol min g(-1)). The prodrug also accumulated rapidly in the liver immediately after injection, resulting in higher concentrations of AZT than observed after administrati on of AZT itself (respective peak concentrations 1.11 and 0.81 mu mol g(-1) ; respective AUCs 42.5 and 12.7 mu mol min g(-1)). Compared with doses of A ZT itself, 3 also led to significantly higher brain concentration of AZT (2 5.7 compared with 9.8 nmol g(-1)) and AUCs (2.8 compared with 1.4 mu mol mi n g(-1)). At the doses used in this study the antifungal agent 2-bromomyris tic acid was measurable in plasma and brain within only 2 min of injection. Hepatic concentrations of 2-bromomyristic acid were higher for at least 2h after dosing with 3 than after dosing with the acid itself. In summary, comparative biodistribution studies of AZT and its prodrug show ed that the prodrug led to higher concentrations of AZT in the brain and li ver. Although the prodrug did not result in measurably different concentrat ions of 2-bromomyristic acid in the blood and brain, it did lead to levels in the liver which were higher than those achieved by dosing with the acid itself.