WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• We have shown previously using the dually perfused isolated human placenta model that the maternal to foetal transfer of the antiviral protease inhibitor drug indinavir is substantially lower than the transfer in the opposite direction. • This finding is not consistent with passive diffusion and indicates that a carriermediated mechanism is involved in retarding the movement in the maternal to foetal direction.• The efflux transporter P-gp located in the apical membrane domain of the placental trophoblast cells has been implicated as the likely cause of the differential bi-directional transport.
WHAT THIS STUDY ADDS• The present study also utilizes the human perfused human isolated placenta to investigate the possible inhibitory effects of the P-gp inhibitor PSC833 and the P-gp substrate/inhibitor ritonavir on the maternal to foetal transfer clearance of indinavir.• The studies, which were conducted such that each placenta served as its own control, demonstrated a statistically significant increase in the maternal to foetal transfer of indinavir in the presence of PSC833 but not in the presence of ritonavir, a protease inhibitor that is often used in combination with other protease inhibitors in dual therapy.• The lack of effect of ritonavir is most likely related to the relatively low inhibitory activity at the clinically relevant concentration used in this study.
AIMSTo investigate the effect of P-gp inhibition on the maternal to foetal transfer of indinavir.
METHODSTerm human placentae (n = 12) were from non-HIV infected women. Maternal to foetal transfer of indinavir was examined in the absence and presence of P-gp inhibitors PSC833 (n = 7) or ritonavir (n = 5), in the perfused human placenta. Antipyrine and [ 3 H]-vinblastine were included as markers of passive diffusion and P-gp transport, respectively. These markers and indinavir were added to maternal perfusate at 0 min; PSC833 or ritonavir was added at 25 min. Steady-state maternal to foetal transfer clearance was calculated during control and inhibitor phases. Indinavir and vinblastine clearances were normalized to antipyrine clearance (clearance index).
RESULTSIndinavir clearance index increased between the control (0.25 Ϯ 0.03) and PSC833 phases (0.37 Ϯ 0.14) (95% CI of the difference -0.23, -0.002). Vinblastine clearance index increased from (0.25 Ϯ 0.08) to (0.34 Ϯ 0.06) in the control and PSC833 phases, respectively (95% CI of difference -0.14, -0.05). Indinavir clearance index was unchanged between control (0.34 Ϯ 0.14) and ritonavir phases (0.39 Ϯ 0.13) (95% CI of the difference -0.19, 0.08). Vinblastine clearance index increased from (0.24 Ϯ 0.12) to (0.32 Ϯ 0.12) in the control and ritonavir phases, respectively (95% CI of the difference -0.15, -0.009).
CONCLUSIONSMaternal to foetal transfer clearance of indinavir and vinblastine increased following P-gp inhibition. The potential role for co-administration of P-gp inhibitors with PIs to reduce perinatal HIV transmission warrants further investigation.
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.
Tonoplast intrinsic proteins (TIPs), belonging to the aquaporin family, are transmembrane channels located mostly at the tonoplast of plant cells. The TIPs are known to transport water and many other small solutes such as ammonia, urea, hydrogen peroxide, and glycerol. In the present review, phylogenetic distribution, structure, transport dynamics, gating mechanism, sub-cellular localization, tissuespecific expression, and co-expression of TIPs are discussed to define their versatile role in plants. Based on the phylogenetic distribution, TIPs are classified into five distinct groups with aromatic-arginine (Ar/R) selectivity filters, typical poremorphology, and tissue-specific gene expression patterns. The tissue-specific
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