The maternal-fetal transfer of lamivudine in the ex vivo human placenta

doi:10.1016/S0002-9378(97)70487-3

American Journal of Obstetrics and Gynecology

Volume 176, Issue 2, February 1997, Pages 291-293

https://doi.org/10.1016/S0002-9378(97)70487-3 Get rights and content

Abstract

OBJECTIVE: Our purpose was to measure the transfer of lamivudine ([-]-2′-deoxy-3′-thiacytidine] across the human placenta both alone and in the presence of zidovudine.

STUDY DESIGN: Nine placentas from term, elective cesarean deliveries were analyzed with use of the ex vivo single cotyledon perfusion system. Antipyrine was used as the reference compound to measure the clearance index values of lamivudine alone and in combination with zidovudine. Lamivudine concentrations in the perfusates and tissues were quantified by high-pressure liquid chromatography.

RESULTS: The clearance index of lamivudine at a maternal concentration of 1.39 μg/ml was 0.23 ± 0.14. At a peak concentration of 14.68 μg/ml the clearance index was 0.14 ± 0.06. These index values did not significantly change in the presence of 1 or 10 μg/ml of zidovudine. In a closed recirculating system the fetal lamivudine concentration increased as more lamivudine was added to the maternal perfusate. The addition of zidovudine did not influence this transfer.

CONCLUSION: Lamivudine appears to cross the placenta by simple diffusion and its transfer does not appear to be altered by zidovudine. (Am J Obstet Gynecol 1997;176:291-30.)

Section snippets

Material and methods

Term placentas were obtained from uncomplicated parturients undergoing elective cesarean deliveries in accordance with the guidelines set by the University of Texas Southwestern Medical Center Institutional Review Board. The placentas were transported to the laboratory in a saline solution within 10 minutes of delivery. The perfusion model used has been previously detailed.6, 7, 8 Briefly, a “fetal circulation” was reestablished by cannulating an artery and a vein on the fetal surface of a

Results

The clearance index of lamivudine at a maternal concentration of 1.39 μg/ml was 0.23 ± 0.14. At a peak maternal concentration of 14.68 μg/ml the clearance index was 0.14 ± 0.06. As illustrated in Table I, these clearance index values did not significantly change in the presence of 1 or 10 μg/ml of zidovudine (p = 0.9372). In addition, the concentration of lamivudine did not appear to influence its clearance index (p = 0.6224).

As also detailed in Table I, with multiple linear regression, the

Comment

The clearance index of lamivudine across the ex vivo human placenta does not appear to be affected by higher doses of lamivudine in the maternal circulation, suggesting a nonsaturable transport mechanism. Furthermore, the addition of zidovudine to the maternal perfusate did not affect the transfer of lamivudine. Our sample size precludes us from stating that there is absolutely no difference in the clearance index values between the two doses. Given our results, however, any difference

References (12)

LC Gilstrap et al.
The transfer of the nucleoside analog ganciclovir across the perfused human placenta
Am J Obstet Gynecol
(1994)
RE Bawdon et al.
The transfer of anti–human immunodeficiency virus nucleoside compounds by the term human placenta
Am J Obstet Gynecol
(1992)
GJ Hart et al.
Effects of (-)-2′-deoxy-3′-thiacytidine (3TC) 5′-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerases alpha, beta, and gamma
Antimicrob Agents Chemother
(1992)
JJ Eron et al.
Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter
N Engl J Med
(1995)
JL Dienstag et al.
A preliminary trial of lamivudine for chronic hepatitis B infection
N Engl J Med
(1995)
Centers for Disease Control and Prevention
Update: AIDS among women-United States, 1994
MMWR Morb Mortal Wkly Rep
(1995)

There are more references available in the full text version of this article.

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At least 80% of pregnant woman in Europe use at least one medication during their pregnancy. The majority of these drugs are prescribed off-label. A better understanding of drug transport and effects in the placenta can provide an improved pharmacological basis to rationalize drug and dose selection for prescription. Here we provide a narrative review of studies that used the ex vivo placenta perfusion model to study placental drug transport and vascular effects of pharmaceuticals. For studies on placental transfer, we found that the methodology used varied substantially between studies as well as the way in which data was reported. Across the different therapeutic groups, ex vivo measurements of transfer generally corresponded well to in vivo findings. Still, further standardization of the perfusion technique would facilitate a broader use of perfusion data, e.g. in the context of quantitative systems pharmacology models as has been explored in recent years. Only few studies investigated the effects of drugs on the vascular tone using the ex vivo dual-side perfusion model. The model was particularly applied to study vasodilatory effects of pharmaceuticals in the fetoplacental circulation. In conclusion, the ex vivo dually perfused human cotyledon provides a relevant system to gain insights in placental drug disposition and study effects on the fetoplacental vasculature.
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Human placenta expresses a variety of ATP-binding cassette (ABC) transporters many of which have been shown to be not only protective against fetal exposure but also important for physiological functions such as nutrient transport. ABC transporters are expressed in all membranes of the fetomaternal barrier of human placenta. Especially important from toxicology point of view are ABCB1/MDR (multidrug resistance)1/P-gp (P-glycoprotein) and ABCG2/BCRP (breast cancer resistance protein), which are expressed on the brush border membrane of syncytiotrophoblast facing maternal blood. As efflux transporters, they transport toxic compounds away from the fetal compartment to the maternal circulation. In animal and placental perfusion studies, it has been shown that inhibition of these transporters increases fetal exposure and fetotoxicity. Several genetic variations in ABC transporter genes have been found but only some of them have been studied on the functional significance to fetal exposure. Because placenta varies more than any other organ between species, human models are important for placental transporter studies. Possibilities include human choriocarcinoma cell lines, isolated primary trophoblastic cells, placental villus cultures, and human placental perfusion, which retains the physiological conditions best of these models. Naturally, in vivo studies would be valuable, but are possible only in the case of clinically necessary drugs and accidental and environmental exposure in pregnant women.
Evaluation of the maternal-fetal transfer of granisetron in an ex vivo placenta perfusion model
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The human placental cotyledon model is an ex vivo model that is an established model for evaluation of potential fetal drug exposure. Bawdon and colleagues have analyzed multiple drugs such as bisheteroypiperazine, lamivudine, zidovudine, azidothymidine, 2′,3′-dideoxyinosine, 2′,3′-dideoxycytidine, and rosiglitazone and determined the amount that crossed the placental/trophoblastic barrier [22–28]. Low sample number and high variability within this model present limitations to this study.
The objective of this study was to estimate maternal–fetal transplacental passage of granisetron in an ex vivo placental perfusion model. Term human placentas (N = 8) were collected immediately after delivery. A single cotyledon from each placenta was perfused granisetron concentration to mimic systemic maternal peak plasma concentrations following either IV (50 ng/mL) or transdermal administration (5 ng/mL). To assess drug transfer and accumulation, samples were collected from maternal and fetal compartments.
In the 50 ng/mL open model, the mean transport fraction was 0.21 ± 0.08 with clearance index of 0.53 ± 0.66. Fetal peak concentrations achieved was 5.6 ± 6.6 ng/mL with mean accumulation of 5.35 ± 6.4 ng/mL. No drug was detected in the fetal compartment with the 5 ng/mL models.
Transplacental passage of granisetron was inconsistent at the 50 ng/mL concentration that achieved with IV dosing. However, there consistently was no detectable passage in all the placentas evaluated of the granisetron at 5 ng/mL concentration that would be achieved after transdermal patch administration.
Utilization of an ex vivo human placental perfusion model to predict potential fetal exposure to carboplatin during pregnancy
2014, American Journal of Obstetrics and Gynecology
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The antipyrine assay was found to be linear over a concentration range of 6.25-100 μg/mL with a correlation coefficient (r) of 0.9981. In the literature placental perfusion studies have included 3 placentas evaluated at each concentration under both conditions of open/open and closed/closed models to determine descriptive statistical parameters such as mean values with SD and coefficient of variance.15-19 The low, middle, and high concentration transfer studies for carboplatin were each performed in 3 placentas for a total of 9 placentas that were included to complete the study.
The objective of this study was to determine the fetal drug compartment concentrations when various concentrations of carboplatin cross the placental-trophoblastic barrier and the effect on the fetal kidneys.
An ex vivo human placenta perfusion model was utilized. Term human placentae (n = 9) were collected immediately after delivery and then reperfused with plasma concentrations achieved with carboplatin an area under the curve of 5 (1000 ng/mL), 7.5 (5000 ng/mL), or 11 (11,000 ng/mL). Antipyrine was used as a reference compound. Samples were collected over 2 hours. Placental transfer was evaluated by computation of transport fraction and clearance index. Primary cells isolated by explant culture of 16-18 week old fetal organ tissues were incubated with carboplatin for up to 48 hours with untreated cell as controls. Immunohistochemical, flow cytometry analysis, and immunoblotting were applied for the expression of apoptosis-related proteins.
Mean transport fractions for carboplatin at low, middle, and high concentrations were 0.05 ± 0.02, 0.04 ± 0.01, and 0.10 ± 0.01, respectively, with clearance indexes of 0.22 ± 0.01, 0.14 ± 0.08, and 0.50 ± 0.07, respectively. The fetal peak concentrations of carboplatin achieved were 61 ± 39 ng/mL (low), 375 ± 248 ng/mL (middle), and 2081 ± 529 ng/mL (high). Fetal kidney cells exposed to carboplatin showed a concentration-dependent increased expression of apoptosis-inducing factor and p53 apoptosis proteins and a time-dependent increase in expression Bax apoptosis protein expression. Apoptosis was confirmed at the high concentration by flow cytometry.
Doses of carboplatin up to an area under the curve of 7.5 were not associated with significant placental transfer, fetal exposure, or fetal toxic effects. This suggests it might not be necessary to empirically reduce carboplatin doses in pregnant women.
Chronic Hepatitis B Virus Infection and Pregnancy
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The 3% rate of congenital anomalies reported in this study also compares favorably to the 2.72% reported by the CDC birth defect surveillance system.74 In pregnant women, lamivudine crosses the placenta readily by simple diffusion.75 In a study of 57 HIV-infected pregnant women receiving lamivudine as part of antiretroviral therapy, maternal blood, cord blood and amniotic fluid samples correlated with fetal concentrations; and the median concentration in the amniotic fluid was 5 times higher than in maternal plasma.76
Planning of pregnancy and management of chronic hepatitis B virus during pregnancy includes recognition of maternal virological status, assessment of liver disease severity and minimization of risk for mother to infant transmission of infection. Decisions regarding the use of antivirals during pregnancy need to be individualized. Monitoring for infection and immunization in newborns is also important. For mothers on antiviral therapy, breastfeeding is not recommended.
Antiretrovirals transfer across the human placenta
2010, Antibiotiques
Le traitement antirétroviral (ARV) des femmes enceintes infectées par le VIH assure le double objectif de la prévention de la transmission périnatale du VIH et du traitement de l’infection maternelle. Le risque de transmission verticale diminuant parallèlement à la charge virale maternelle, les combinaisons d’ARV présentent une efficacité antivirale supérieure à celle obtenue par les monothérapies. L’exploration du passage transplacentaire de ces composés constitue un point crucial dans l’évaluation des risques de la grossesse. Les études réalisées in vivo et ex vivo ont mis en évidence le transfert maternofœtal rapide des inhibiteurs nucléos(t)idiques de la transcriptase inverse (INTI), suggérant un passage par simple diffusion. Aux concentrations thérapeutiques étudiées, les indices de clairance des inhibiteurs de la protéase (IP) sont très faibles et aucune accumulation intraplacentaire n’a été mise en évidence. Le faible passage transplacentaire des IP a été confirmé in vivo et peut s’expliquer en partie par une fixation protéique et une liposolubilité élevées de ces composés (à l’exception de l’indinavir qui présente un bon transfert placentaire). À l’opposé, le rapport maternofœtal de la névirapine, inhibiteur non nucléosidique de la transcriptase inverse avoisine l’unité, traduisant un important passage transplacentaire. Enfin, les quelques études menées et les caractéristiques physicochimiques et pharmacocinétiques des nouvelles molécules montrent un passage transplacentaire négligeable pour enfuvirtide, intermédiaire pour maraviroc et raltégravir et important pour ténofovir et emtricitabine.
HIV-infected pregnant women should be offered antiretroviral (ARV) prophylaxis to prevent perinatal HIV transmission, as well as optimal therapies for their own health. Since the risk of vertical transmission decreases with lower maternal viral load, combination therapies exhibit a more pronounced antiviral efficacy than monotherapy in preventing such transmission. The investigation of placental transfer remains one of the cornerstones of pregnancy risk assessment. In vivo and ex vivo studies have established that maternal-fetal transfer of nucleoside analogs occurs rapidly suggesting a simple diffusion mechanism. The clearance index of HIV protease inhibitors (PI) at therapeutic levels is extremely low, with no accumulation in placental tissue. The low HIV PI placental transfer has been confirmed by in vivo studies and can be explained by their high plasma protein binding and liposolubility (except for indinavir whose placental transfer is high). In contrast with these findings, the nevirapine (non-nucleoside reverse transcriptase inhibitor) maternal/cord blood ratio averaged unity, indicating a high placental transfer. Finally some studies, physical-chemistry and pharmacokinetics properties regarding new drugs, show no enfuvirtide placental transfer, intermediate transfer of maraviroc and raltegravir and a high transfer of tenofovir and emtricitabine.

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^☆: From the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center.

^☆☆: Reprint requests: Steven L. Bloom, MD, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9032.

^★: 6/1/78820

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The maternal-fetal transfer of lamivudine in the ex vivo human placenta☆,☆☆,★

Abstract

Section snippets

Material and methods

Results

Comment

Am J Obstet Gynecol

Am J Obstet Gynecol

Effects of (-)-2′-deoxy-3′-thiacytidine (3TC) 5′-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerases alpha, beta, and gamma

Antimicrob Agents Chemother

Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter

N Engl J Med

A preliminary trial of lamivudine for chronic hepatitis B infection

N Engl J Med

Update: AIDS among women-United States, 1994

MMWR Morb Mortal Wkly Rep