To determine whether lower umbilical cord than maternal binding of indinavir and saquinavir contributed to the low cord: maternal (C: M) total concentration ratios reported previously.Methods
Indinavir and saquinavir unbound fraction (fu) was determined using equilibrium dialysis. Buffer solutions of human serum albumin (HSA) (20.0, 30.0, 40.0 g l−1) and α1-acid glycoprotein (AAG) (0.20, 0.60, 2.00 g l−1) were spiked with indinavir (1.00 and 8.00 mg l−1) or saquinavir (0.15 and 1.50 mg l−1). Matched maternal and umbilical cord plasma was spiked with 1.00 mg l−1 indinavir (n = 12) or 0.15 mg l−1 saquinavir (n = 20). Spiked protein/plasma solutions were dialyzed against isotonic phosphate buffer, at 37 °C. At equilibrium, indinavir and saquinavir concentrations were quantified, and the fu determined.Results
Indinavir and saquinavir demonstrated protein concentration-dependent binding in buffer solutions of HSA and AAG. Indinavir fu was significantly higher in umbilical cord (0.53 ± 0.12) compared with maternal (0.36 ± 0.11) plasma (95% CI of the difference −0.26, −0.097). Similarly, saquinavir fu was different between umbilical cord (0.0090 ± 0.0046) and maternal plasma (0.0066 ± 0.0039) (95% CI of the difference −0.0032, −0.0016). The transplacental AAG concentration gradient contributed significantly to the binding differential of both drugs.Conclusions
The differential plasma binding of both drugs, which was largely the result of the transplacental AAG concentration gradient, would contribute to the low C: M total plasma concentration ratios observed previously. Unbound concentrations of indinavir and saquinavir are likely to be substantially lower in umbilical cord than maternal plasma.