Inhibition of placental P‐glycoprotein: impact on indinavir transfer to the foetus

• Published in: British journal of clinical pharmacology Vol. 65; no. 5; pp. 667 - 673
• Main Authors: Sudhakaran, Sreeja, Rayner, Craig R., Li, Jian, Kong, David C. M., Gude, Neil M., Nation, Roger L.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2008; Blackwell Science; Blackwell Science Inc
• Subjects: ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; Biological and medical sciences; Biological Transport - drug effects; Clinical Pharmacology in Pregnancy; Female; HIV Infections - prevention & control; HIV protease inhibitors; HIV Protease Inhibitors - pharmacokinetics; Human immunodeficiency virus; Humans; indinavir; Indinavir - pharmacokinetics; Maternal-Fetal Exchange - drug effects; Medical sciences; Pharmacology. Drug treatments; Placenta - chemistry; placental transfer; Pregnancy; P‐glycoprotein; Ritonavir - pharmacokinetics; Antiretroviral agent; Fetal membrane; Enzyme; Placental transfer; P Glycoprotein; Enzyme inhibitor; P-glycoprotein; Peptidases; Placenta; HIV protease inhibitors; Hydrolases; Antiviral; Indinavir; Protease inhibitor
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/j.1365-2125.2007.03067.x

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 carrier‐mediated 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. AIMS To investigate the effect of P‐gp inhibition on the maternal to foetal transfer of indinavir. METHODS Term 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 [3H]‐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). RESULTS Indinavir clearance index increased between the control (0.25 ± 0.03) and PSC833 phases (0.37 ± 0.14) (95% CI of the difference −0.23, −0.002). Vinblastine clearance index increased from (0.25 ± 0.08) to (0.34 ± 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 ± 0.14) and ritonavir phases (0.39 ± 0.13) (95% CI of the difference −0.19, 0.08). Vinblastine clearance index increased from (0.24 ± 0.12) to (0.32 ± 0.12) in the control and ritonavir phases, respectively (95% CI of the difference −0.15, −0.009). CONCLUSIONS Maternal 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.