Placental transfer of lopinavir/ritonavir in the ex vivo human cotyledon perfusion model

Gavard, Laurent; Gil, Sophie; Peytavin, Gilles; Ceccaldi, Pierre-François; Ferreira, Claudia; Farinotti, Robert; Mandelbrot, Laurent

doi:10.1016/j.ajog.2006.01.017

Cited by 47 publications

(34 citation statements)

References 22 publications

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“…Studies using the human cotyledon perfusion model have shown that albumin plays a major role in placental LPV transfer (Gavard et al, 2006;Ceccaldi et al, 2010). For example, Gavard et al (2006) demonstrated that LPV transfer was 23.6 Ϯ 6.9% at an albumin concentration of 2 g/l, 20.7 Ϯ 10% at 10 g/l, and only 3.3 Ϯ 0.5% at 40 g/l. The data of Gavard et al (2006) predict higher transfer in our GDM group (15%) than that in our control groups (6 -7%), which is not what we observed.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of placental transporter data, this finding would be surprising given the GDM group's decreased albumin concentrations and decreased LPV protein binding. Studies using the human cotyledon perfusion model have shown that albumin plays a major role in placental LPV transfer (Gavard et al, 2006;Ceccaldi et al, 2010). For example, Gavard et al (2006) demonstrated that LPV transfer was 23.6 Ϯ 6.9% at an albumin concentration of 2 g/l, 20.7 Ϯ 10% at 10 g/l, and only 3.3 Ϯ 0.5% at 40 g/l.…”

Section: Discussionmentioning

confidence: 99%

“…Although the protease inhibitors RTV, indinavir, and saquinavir have low cord blood-to-maternal blood ratios that range from 0 to 0.01 (Chappuy et al, 2004), LPV has been found to have a comparatively high ratio of 0.2 Ϯ 0.13 (Stek et al, 2006). More importantly, Gavard et al (2006) demonstrated in the human cotyledon perfusion model that this ratio leads to fetal compartment concentrations that exceed the 50% HIV inhibitory concentration for LPV under normal physiological conditions (Abbott Laboratories Ltd., 2010). The fact that fetal exposure was reduced in STZ-induced GDM raises questions about GDM's potential impact on vertical HIV transmission risk and could warrant clinical investigation.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Gavard et al (2006) demonstrated that LPV transfer was 23.6 Ϯ 6.9% at an albumin concentration of 2 g/l, 20.7 Ϯ 10% at 10 g/l, and only 3.3 Ϯ 0.5% at 40 g/l. The data of Gavard et al (2006) predict higher transfer in our GDM group (15%) than that in our control groups (6 -7%), which is not what we observed.…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Anger

Piquette-Miller²

2011

Drug Metab Dispos

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ABSTRACT:Lopinavir (LPV) is the preferred HIV protease inhibitor in pregnancy, but it is unknown if gestational diabetes mellitus (GDM) affects its disposition. Hepatic protein expression and plasma protein binding are altered in rodent models of GDM. Because LPV is influenced by hepatic transporters and metabolic enzymes and is highly protein bound, it was hypothesized that streptozotocininduced GDM would alter its disposition. Maternal and fetal tissues were collected from GDM rats and controls 45 min after LPV injection. In another cohort, fetuses were serially extracted 5 to 60 min after injection. LPV was quantified using liquid chromatography tandem mass spectrometry. Expression of relevant transporters, such as Multidrug resistance protein 1 (Mdr1), and cytochrome P450 3a2 (Cyp3a2), which metabolizes LPV in rodents, was measured in maternal liver via quantitative reverse transcriptase polymerase chain reaction and Western blot analysis. Expression of relevant transporters also was measured in placenta via quantitative reverse transcriptase polymerase chain reaction. Protein binding was determined by ultrafiltration. Relative to controls, we observed dramatically reduced maternal and fetal LPV exposure in GDM. Compared with controls, maternal hepatic Mdr1 and Cyp3a2 were up-regulated, and protein binding was reduced in the GDM group. Increased Mdr1-and Cyp3a2-mediated hepatobiliary clearance, coupled with a larger unbound LPV fraction, is likely to have facilitated hepatic elimination, thereby decreasing maternal and fetal exposure. Not surprisingly, up-regulation of Mdr1 and Cyp3a2's transcriptional regulator, pregnane X receptor, was demonstrated in maternal liver via Western blot analysis. Up-regulation of Mdr1 in placentas isolated from the GDM group likely also contributed to decreased fetal exposure to LPV. This study provides preclinical support for an as yet unreported drug-disease (LPV-GDM) interaction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Anger

Piquette-Miller²

2011

Drug Metab Dispos

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“…Nucleoside reverse transcriptase in- (25,26). Interestingly, protease inhibitors, which have higher molecular weights and are more lipophilic than maraviroc, present even lower placental transfer (MW ϭ 671 Da and CLI ϭ 0.05 for saquinavir; MW ϭ 629 Da and CLI ϭ 0.10 for lopinavir) (21,27). We then investigated whether ABC transporters could be involved in the weak maraviroc placental transfer we observed.…”

Section: Discussionmentioning

confidence: 99%

Placental Transfer of Maraviroc in an Ex Vivo Human Cotyledon Perfusion Model and Influence of ABC Transporter Expression

Vinot

Gavard

Tréluyer

et al. 2013

Antimicrob Agents Chemother

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f Nowadays, antiretroviral therapy is recommended during pregnancy to prevent mother-to-child transmission of HIV. However, for many antiretroviral drugs, including maraviroc, a CCR5 antagonist, very little data exist regarding placental transfer. Besides, various factors may modulate this transfer, including efflux transporters belonging to the ATP-binding cassette (ABC) transporter superfamily. We investigated maraviroc placental transfer and the influence of ABC transporter expression on this transfer using the human cotyledon perfusion model. Term placentas were perfused ex vivo for 90 min with maraviroc (600 ng/ ml) either in the maternal-to-fetal (n ‫؍‬ 10 placentas) or fetal-to-maternal (n ‫؍‬ 6 placentas) direction. Plasma concentrations were determined by ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Fetal transfer rates (FTR) and clearance indexes (CLI) were calculated as ratios of fetal to maternal concentrations at steady state (mean values between 30 and 90 min) and ratios of FTR of maraviroc to that of antipyrine, respectively. ABC transporter gene expression levels were determined by quantitative reverse transcription (RT)-PCR and ABCB1 protein expression by Western blotting. For the maternal-to-fetal direction, the mean FTR and CLI were 8.0% ؎ 3.0 and 0.26 ؎ 0.07, respectively, whereas the mean CLI was 0.52 ؎ 0.23 for the fetal-to-maternal direction. We showed a significant inverse correlation between maraviroc CLI and ABCC2, ABCC10, and ABCC11 placental gene expression levels (P < 0.05). To conclude, we report a low maraviroc placental transfer probably involving ABC efflux transporters and thus in all likelihood associated with a limited fetal exposition. Nevertheless, these results would need to be supported by in vivo data obtained from paired maternal and cord blood samples.

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Transplacental transfer of Remdesivir and GS‐441524: An ex vivo perfusion study

Louchet,

Ribot,

Bouazza

et al. 2023

Health Science Reports

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Placental transfer of lopinavir/ritonavir in the ex vivo human cotyledon perfusion model

Cited by 47 publications

References 22 publications

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Placental Transfer of Maraviroc in an Ex Vivo Human Cotyledon Perfusion Model and Influence of ABC Transporter Expression

Transplacental transfer of Remdesivir and GS‐441524: An ex vivo perfusion study

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