In vivo maternal-fetal pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) in pigtailed macaques (Macaca nemestrina)

Abstract

To determine whether stavudine (2',3'-didehydro-3'-deoxythymidine) is actively transported in vivo across the placenta and to determine the extent of its transfer, stavudine was administered as an intravenous bolus to four near-term macaques (Macaca nemestrina) (5 mg/kg of body weight via the femoral vein) or to their fetuses (10 mg/kg via the carorid artery) at gestational age 134 +/- 5 days, with the administrations about 1 week apart. Antipyrine (a passive diffusion marker) was always coadministered (20 mg/kg) with stavudine. Samples of maternal and fetal plasma and amniotic fluid were collected at frequent intervals up to 240 min after the dose. In a separate experiment, three animals received stavudine for 30 h at a low rate of infusion (22 micrograms/min/kg via the femoral vein) to the dam or at a 10-fold-higher rate of infusion (220 micrograms/min/kg), separated by at least one week, in order to determine if the transplacental transfer of stavudine is saturable. Antipyrine (41.7 micrograms/min/kg) was coinfused with stavudine. Samples of maternal and fetal plasma and amniotic fluid were collected at regular intervals for up to 30 h. The concentrations of stavudine and antipyrine were determined by high-performance liquid chromatography. The transplacental maternal-fetal drug clearances were compared by the paired Student t test. The clearance associated with maternal-fetal transfer of the drug (CLdf) (0.54 +/- 0.08 ml/min/kg) was not significantly different (P > 0.05) from the clearance associated with fetal-maternal transfer of the drug, CLfd (0.66 +/- 0.11 ml/min/kg). Also, CLdf was not significantly different (P > 0.05) from CLfd when normalized with respect to the corresponding transplacental clearance of antipyrine (0.23 +/- 0.04 versus 0.36 +/- 0.25). The ratios of the steady-state plasma stavudine concentration in the fetus to that in the dam were 0.77 +/- 0.06 at the low stavudine infusion rate and 0.81 +/- 0.09 at the high stavudine infusion rate. The obtained data indicate that transfer of stavudine across the placenta is passive and constant over the dose range studied.