Differential protein binding of indinavir and saquinavir in matched maternal and umbilical cord plasma

Abstract

Aims: 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. © 2006 The Authors.