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Differential protein binding of indinavir and saquinavir in matched maternal and umbilical cord plasma
Author(s) -
Sudhakaran Sreeja,
Rayner Craig R.,
Li Jian,
Kong David C. M.,
Gude Neil M.,
Nation Roger L.
Publication year - 2007
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2006.02766.x
Subject(s) - saquinavir , indinavir , transplacental , umbilical cord , chemistry , blood proteins , fetus , medicine , biochemistry , pregnancy , placenta , biology , immunology , sida , human immunodeficiency virus (hiv) , viral disease , viral load , antiretroviral therapy , genetics
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 ( f u) was determined using equilibrium dialysis. Buffer solutions of human serum albumin (HSA) (20.0, 30.0, 40.0 g l −1 ) and α 1 ‐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 f u determined. Results Indinavir and saquinavir demonstrated protein concentration‐dependent binding in buffer solutions of HSA and AAG. Indinavir f u 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 f u 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.