| A new high performance liquid chromatographic (HPLC) assay for the analysis of 3'-azido-3'-deoxythymidine (AZT) in rat placenta fetus and placenta was developed. A new HPLC assay for the analysis of the anti-retroviral prodrug dipalmitoyl-phosphatidyl-3 '-azido-3'-deoxythymidine (DPPAZT) in rat plasma, amniotic fluid, fetus and placenta was also developed. Accuracy and precision for both HPLC methods was well within acceptable limits (<10%).;The effects of liposomal encapsulation on the disposition and placental transfer of AZT in the pregnant rat was investigated. Multilamellar liposomes with a net negative charge containing AZT were prepared and administered to near-term pregnant rats. Pregnant rats received either a 25 mg/kg dose of AZT entrapped in liposomes or in solution. Samples of plasma, amniotic fluid, placenta and fetus were analyzed by HPLC. Liposomal entrapment of AZT delayed elimination in the dam, as half-life and mean residence time were significantly increased. Time to peak AZT concentration in fetus and placenta was not affected by liposomal encapsulation. Higher concentrations were maintained for longer periods of time in maternal plasma, placenta, and fetus. Relative exposure of the placenta to AZT was significantly increased. Relative exposure of the fetus to AZT was increased, but not deemed significant.;The effects of gender and pregnancy on the disposition of DPPAZT and AZT after DPPAZT administration were investigated. Male, female, and pregnant rats received a 16.4 mg/kg intravenous dose of DPPAZT. Plasma samples; were taken and analyzed separately by HPLC for DPPAZT and AZT. There were no significant differences in the pharmacokinetics of DPPAZT or AZT after DPPAZT administration due to gender. The area under the curve (AUC) and half- life of DPPAZT was significantly larger in the pregnant rat and DPPAZT clearance was significantly lower. The rate of formation of AZT from DPPAZT was significantly lower in the pregnant rat. AUC and half-life for AZT were significantly larger in the pregnant rat, and volume and clearance were significantly lower.;Due to the prolonged exposure of the pregnant rat to AZT using these phospholipid formulations, they may prove to be useful for the treatment of pregnant HIV positive patients and the reduction of HIV vertical transmission. |
