Influence of P‐Glycoprotein on the Transplacental Passage of Cyclosporine

Pávek, Petr; Fendrich, Z.; Štaud, František; Maláková, Jana; Brozmanová, Hana; Lázníček, Milan; Semecký, Vladimír; Grundmann, Milan; Palička, Vladimír

doi:10.1002/jps.1108

Cited by 64 publications

(36 citation statements)

References 32 publications

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“…In our previous study (Pavek et al, 2001), we also demonstrated that sodium azide (5 mM) increased the transplacental paracellular passage of L-[ 3 H]glucose in later intervals, which could suggest impairment of the placental barrier. Therefore, we conducted experiments with sodium azide only for 27 min after catheterization.…”

Section: Materials Andsupporting

confidence: 54%

“…The method of dually perfused rat placenta was used as described previously (Mohammed et al, 1993;Pavek et al, 2001). Briefly, the placenta was excised and allowed to dive in the heated Ringer saline.…”

Section: Materials Andmentioning

confidence: 99%

“…Perfusion experiments did not last longer than 36 min, because the integrity of the placental barrier could be affected in later intervals. This notion is based on our previous experiments with L-[ 3 H]glucose, a marker of paracellular diffusion, where the transplacental passage of L-[ 3 H]glucose started to significantly increase in later intervals of the perfusion (Pavek et al, 2001). Wet weights of the placentas used in experiments were 0.54 Ϯ 0.13 g.…”

Section: Materials Andmentioning

confidence: 99%

“…Our previous results suggested that inhibition of P-gp was more significant when an inhibitor of P-gp was present in the maternal compartment rather than in the fetal one (Pavek et al, 2001). That is why the inhibitors/modulators of P-gp were given into the maternal solution even in the feto-maternal experiments.…”

Section: Materials Andmentioning

confidence: 99%

“…Our previous in situ experiments demonstrated that the passage of CsA across the rat placenta is restricted in the materno-fetal direction due to the P-gp activity (Pavek et al, 2001).…”

mentioning

confidence: 99%

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Examination of the Functional Activity of P-glycoprotein in the Rat Placental Barrier Using Rhodamine 123

Pávek

Štaud²,

Fendrich³

et al. 2003

J Pharmacol Exp Ther

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Rhodamine 123 (Rho123), a model substrate of P-glycoprotein (P-gp), was used to evaluate the functional activity of P-gp efflux transporter in the rat placental barrier. The dually perfused rat-term placenta method was used. In our experiments, the materno-fetal transplacental passage of Rho123 did not meet the criteria of the first-order pharmacokinetics, suggesting an involvement of transporter-mediated process. Inhibitors of P-gp, such as [3Ј-keto-Bmt 1 ]-[Val 2 ]-cyclosporine (PSC833), cyclosporine (CsA), quinidine, and chlorpromazine, increased significantly the materno-fetal transplacental passage of Rho123 in the experiments under steady-state conditions. On the other hand, PSC833, CsA, and quinidine decreased the feto-maternal passage of Rho123. Similarly, in the experiments carried out under nonsteady-state conditions, CsA accelerated the passage of Rho123 in the materno-fetal direction and decreased its passage in the opposite direction. Feto-maternal transplacental clearances of Rho123 were found to be considerably higher than those in the materno-fetal course. Potent P-gp inhibitors, such as PSC833 or CsA, partially canceled the asymmetry. Negligible metabolism of Rho123 into its major demethylated metabolite rhodamine 110 was observed in the rat placenta. Expression of P-gp genes was detected using immunohistochemical, Western blotting, and reverse transcription-polymerase chain reaction methods preferentially in the second rat syncytiotrophoblast layer. In conclusion, these data suggest that P-gp limits the entry of Rho123 into fetuses and at the same time it accelerates the feto-maternal elimination of the model compound. Therefore, it seems plausible that pharmacokinetics of xenobiotics in the rat placental barrier could be controlled by P-gp in both directions.

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Section: Materials Andsupporting

confidence: 54%

Section: Materials Andmentioning

confidence: 99%

Section: Materials Andmentioning

confidence: 99%

Section: Materials Andmentioning

confidence: 99%

“…Our previous in situ experiments demonstrated that the passage of CsA across the rat placenta is restricted in the materno-fetal direction due to the P-gp activity (Pavek et al, 2001).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Examination of the Functional Activity of P-glycoprotein in the Rat Placental Barrier Using Rhodamine 123

Pávek

Štaud²,

Fendrich³

et al. 2003

J Pharmacol Exp Ther

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Influence of Changes in Physiology, Transporters, and Enzyme Expression on Disposition and Metabolism of Drugs during Pregnancy and Clinical Implications

Jhajra

Singh

Holm³

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

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Safe and effective administration of drugs during pregnancy is a challenge due to physiological changes in the mother and limited development of the mechanisms of metabolism of xenobiotics in the fetus. In particular, concentrations of transporters such as PgP, BCRP, MRP3, OCT3, and OCTN1 change in the mother's placenta and fetal tissues with advancing gestation, confounding standard therapies. Drug‐metabolizing enzymes in the placenta and developing fetus differ from those in the liver of the mother. For example, CYP3A7 is the predominant CYP3A isoform in the fetus, while CYP3A4 is predominant in adults. These isoforms have different substrates and kinetics, and thus, challenges to the fetus can be very different. Hence, there is a need for selectivity in administration of drugs and for titrating the dose to maintain efficacy and/or minimize side effects during pregnancy. This is particularly important for drugs with a narrow therapeutic window or those with marked pharmacologic or toxicological outcomes, and also for drugs that are metabolized predominantly by a single enzyme or transporter. Before initiating any new drug regimen during pregnancy, there is the need for systemic monitoring of plasma concentrations for exposure, especially during the initial days of therapy. It is anticipated that with the advancement of understanding of drug metabolism and transport in the placenta and fetus, the potential for making early predictions with respect to effect and tolerance of drugs may be possible, resulting in safer drug therapies for both pregnant mothers and fetus.

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