Transfer of acipimox across the isolated perfused human placenta

Ghabrial, Hany; Czuba, M A; Stead, Cheryl K.; Smallwood, Richard A.; Morgan, Denis J.

doi:10.1016/0143-4004(91)90499-6

Cited by 10 publications

(5 citation statements)

References 18 publications

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“…The P‐gp inhibitors, PSC833 and ritonavir, did not interfere with the chromatography of indinavir or the internal standard, verapamil. Perfusate antipyrine concentrations were determined using a validated HPLC assay [25]. The measured concentrations of the QC samples (0.50, 5.00 and 20.0 mg l −1 ) were within 10% of the nominal concentrations and reproducibility was also within 10% for all QC samples.…”

Section: Methodsmentioning

confidence: 99%

“…For the low QC, the corresponding values were within 20%.The P-gp inhibitors, PSC833 and ritonavir, did not interfere with the chromatography of indinavir or the internal standard, verapamil. Perfusate antipyrine concentrations were determined using a validated HPLC assay [25].The measured concentrations of the QC samples (0.50, 5.00 and 20.0 mg l -1 ) were within 10% of the nominal concentrations and reproducibility was also within 10% for all QC samples.The chromatography of antipyrine and internal standard, phenacetin, was not influenced by PSC833 or ritonavir. [ 3 H]-Vinblastine concentrations in perfusate were analyzed using liquid scintillation counting (PackardTricarb 1900CA scintillation counter).…”

Section: Drug Analysismentioning

confidence: 98%

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

Sudhakaran

Rayner

et al. 2007

Brit J Clinical Pharma

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Drug Analysismentioning

confidence: 98%

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

Sudhakaran

Rayner

et al. 2007

Brit J Clinical Pharma

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“…Perfusate antipyrine concentrations were determined by using the HPLC assay of Ghabrial et al (13). The measured concentrations of the QC samples (0.5, 5.0, and 20.0 mg/liter) were within 8% of the nominal concentrations, and reproducibility was also within 8% for all QCs.…”

Section: Methodsmentioning

confidence: 99%

“…The dual in vitro perfusion of the isolated human placenta was based on the method of Penfold et al (30) and subsequently modified by our group (7,8,13). Briefly, placentae were obtained within 5 min of delivery, and independent fetal and maternal circulations were established in a single, nontraumatized peripheral cotyledon within 20 min.…”

Section: Methodsmentioning

confidence: 99%

Differential Bidirectional Transfer of Indinavir in the Isolated Perfused Human Placenta

Sudhakaran

Ghabrial

Nation

et al. 2005

Antimicrob Agents Chemother

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“…In our experiments, we cannot rule out a direct effect of acipimox on fetal growth by crossing the placenta. In fact in human placenta perfusates, acipimox crossed the placenta at a slow rate [18].…”

Section: Figurementioning

confidence: 99%

Effect of Acipimox on Plasma Lipids and Glucose/Insulin in Pregnant Rats

Sánchez-Vera

Bonet

Viana

et al. 2002

Journal of Diabetes Research

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To determine how a reduction in maternal hypertriglyceridemia during late pregnancy may affect glucose/insulin relationships, pregnant and virgin rats were orally treated with acipimox, a potent antilipolytic agent. In 20-day pregnant rats receiving 80 mg of acipimox, plasma triglycerides (TG), free fatty acids (FFA), and glycerol decreased more than in virgin rats shortly after the drug (up to 7 hours), when compared with animals treated with distilled water, whereas plasma glucose level was unaffected by the treatment in either group of rats. When acipimox was given every 12 hours from day 17 to day 20 of pregnancy, plasma TG, FFA, and glycerol levels progressively increased, whereas they either decreased or did not change in virgin rats receiving the same treatment, with no effect in plasma glucose levels in either group. Fetal body weight was lower than in controls in 20-day pregnant rats that received acipimox for 3 days. On day 20 of pregnancy, 3 hours after receiving acipimox or distilled water, rats received a 2 g glucose/kg oral load and it was found that the change in plasma glucose was similar in both groups, whereas the increase in plasma insulin was greater in pregnant rats treated with acipimox. However, no difference was found in either variable after the oral glucose load in virgin rats receiving acipimox or distilled water. No differences in plasma glucose levels were found after intravenous (IV) administration of insulin in pregnant rats treated or not treated with acipimox. In conclusion, present results show that administration of acipimox during the last days of gestation inhibited lipolysis and decreased fetal weight. Over a short period of time, in pregnant rats, reductions of plasma FFA and TG after acipimox treatment improved the glucose-induced insulin release, but did not seem to have any effect in peripheral insulin resistance. The enhanced lipolytic activity present during late gestation gives rise to an elevation in plasma free fatty acids (FFA) and triglycerides (TG), both in women and rats [1][2][3]. Some tissues use fatty acids as fuel, sparing glucose for the fast-growing fetus and those maternal tissues that can only use glucose as fuel energy [4]. The mechanisms involved in this elevated lipolytic activity are uncertain, but the rising levels of placental lactogen and the insulin resistance during late pregnancy seem to play a relevant role [5][6][7].The enhanced availability of FFA to the liver seems to contribute to the increased production of TG by this organ [8] and therefore to the development of maternal hypertriglyceridemia. Exaggerated increment of TG in maternal circulation may be involved in some of the pregnancy-induced complications, including eclampsia [9] and insulin resistance that would cause the development of gestational diabetes [7], 2 of the most common pregnancy-induced complications. Therefore, decreasing the hypertriglyceridemia of late pregnancy may be of therapeutic use. Nevertheless, this therapeutic approach may not be risk free for the fetus, becaus...

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Transfer of acipimox across the isolated perfused human placenta

Cited by 10 publications

References 18 publications

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

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

Differential Bidirectional Transfer of Indinavir in the Isolated Perfused Human Placenta

Effect of Acipimox on Plasma Lipids and Glucose/Insulin in Pregnant Rats

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