Multiple drug transporters mediate the placental transport of sulpiride

Bai, Mengru; Ma, Zhiyuan; Sun, Dawei; Zheng, Caihong; Weng, Yuanyuan; Yang, Xi; Jiang, Ting; Jiang, Huidi

doi:10.1007/s00204-017-2008-8

Cited by 32 publications

(12 citation statements)

References 44 publications

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“…Our study clearly demonstrated that sulpiride was a substrate of hOCTN1 (K m of 249.5 ± 36 μ m ) and hOCTN2 (K m of 234.7 ± 35 μ m ) using MDCK cells stably expressing hOCTN1 or hOCTN2 (Figures and ; Table ), which was in accordance with our previous study (Bai et al, ). However, a previous study reported that sulpiride was not a substrate of hOCTN1 or hOCTN2 in transiently transfected cells (Dos Santos Pereira et al, ), which might be attributed to the alteration or loss of the function of hOCTNs in their applied cells during the experiment.…”

Section: Discussionsupporting

confidence: 93%

“…(a) MDCK-hOCTN1/2 and mock cells were incubated in UpB (pH 6.4) with sulpiride (10-500 μM, 10 min); (b) MDCK-hOCT2 and mock cells were incubated in HBSS with sulpiride (5-500 μM, 10 min); (c) MDCK-hMATE1 and mock cells were incubated in AUB with sulpiride (1-100 μM, 2 min); (d) MDCK-hMATE2-K and mock cells in AUB with sulpiride (0.5-50 μM, 2 min) at 37°C. Data are expressed as mean ± SD, n = 3 Table 1), which was in accordance with our previous study (Bai et al, 2017). However, a previous study reported that sulpiride was not a substrate of hOCTN1 or hOCTN2 in transiently transfected cells (Dos Santos Pereira et al, 2014), which might be attributed to the alteration or loss of the function of hOCTNs in their applied cells during the experiment.…”

Section: Sulpiride Accumulation In Isolated Mouse Primary Renal Tubsupporting

confidence: 89%

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Multiple organic cation transporters contribute to the renal transport of sulpiride

Weng

Wang

et al. 2017

Biopharm & Drug Disp

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Sulpiride, a selective dopamine D2 receptor blocker, is used widely for the treatment of schizophrenia, depression and gastric/duodenal ulcers. Because the great majority of sulpiride is positively charged at physiological pH 7.4, and ~70% of the dose recovered in urine is in the unchanged form after human intravenous administration of sulpiride, it is believed that transporters play an important role in the renal excretion of sulpiride. The aim of the present study was to explore which transporters contribute to the renal disposition of sulpiride. The results demonstrated that sulpiride was a substrate of human carnitine/organic cation transporter 1 (hOCTN1) and 2 (hOCTN2), human organic cation transporter 2 (hOCT2), human multidrug and toxin efflux extrusion protein 1 (hMATE1) and 2-K (hMATE2-K). Sulpiride accumulation from the basolateral (BL) to the apical (AP) side in MDCK-hOCT2/pcDNA3.1 cell monolayers was much greater than that in MDCK-hOCT2/hMATE1 cells, and cimetidine dramatically reduced the intracellular accumulation of sulpiride from BL to AP. In addition, the accumulation of sulpiride in mouse primary renal tubular cells (mPRTCs) was markedly reduced by inhibitors of Oct2 and Octns. The results implied that OCTN1, OCTN2, OCT2, MATE1 and MATE2-K probably contributed to the renal transfer of sulpiride, in which OCT2 mediated the uptake of sulpiride from the bloodstream to the proximal tubular cells, while MATEs contributed to the sulpiride efflux from the proximal tubular cells to the renal lumen, and OCTNs participated in both renal secretion and reabsorption.

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Section: Discussionsupporting

confidence: 93%

Section: Sulpiride Accumulation In Isolated Mouse Primary Renal Tubsupporting

confidence: 89%

Multiple organic cation transporters contribute to the renal transport of sulpiride

Weng

Wang

et al. 2017

Biopharm & Drug Disp

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“…MDCK-hOCTN2 cells were seeded into 24-well plates at a density of 2 Â 10 5 /well. On day 3 after seeding, cellular accumulation experiments were performed with the method described by our laboratory (Bai et al, 2017;Ma et al, 2017). Cells were washed twice and preincubated with Krebs-Ringer-Henseleit buffer for 10 minutes at 37°C, then 200 ml of Krebs-Ringer-Henseleit buffer containing The Mechanism of Maternal Plasma L-Carnitine Reduction d 3 -L-Car with or without pregnancy-related hormones (E2, P4, CORT, and cortisol) was added to initiate accumulation for 3 minutes.…”

Section: Methodsmentioning

confidence: 99%

Maternal Plasma l-Carnitine Reduction During Pregnancy Is Mainly Attributed to OCTN2-Mediated Placental Uptake and Does Not Result in Maternal Hepatic Fatty Acid β-Oxidation Decline

Bai

Zeng

Chen

et al. 2019

Drug Metabolism and Disposition

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L-Carnitine (L-Car) plays a crucial role in fatty acid b-oxidation. However, the plasma L-Car concentration in women markedly declines during pregnancy, but the underlying mechanism and its consequences on maternal hepatic b-oxidation have not yet been clarified. Our results showed that the plasma L-Car level in mice at gestation day (GD) 18 was significantly lower than that in nonpregnant mice, and the mean fetal-to-maternal plasma L-Car ratio in GD 18 mice was 3.0. Carnitine/organic cation transporter 2 (OCTN2) was highly expressed in mouse and human placenta and upregulated as gestation proceeds in human placenta, whereas expressions of carnitine transporter (CT) 1, CT2, and amino acid transporter B 0,+ were extremely low. Further study revealed that renal peroxisome proliferator-activated receptor a (PPARa) and OCTN2 were downregulated and the renal L-Car level was reduced, whereas the urinary excretion of L-Car was lower in late pregnant mice than in nonpregnant mice. Meanwhile, progesterone (pregnancy-related hormone) downregulated the expression of renal OCTN2 via PPARa-mediated pathway, and inhibited the activity of OCTN2, but estradiol, corticosterone, and cortisol did not. Unexpectedly, the maternal hepatic level of L-Car and b-hydroxybutyrate (an indicator of mitochondrial b-oxidation), and mRNA levels of several enzymes involved in fatty acid b-oxidation in GD 18 mice were higher than that in nonpregnant mice. In conclusion, OCTN2 mediated L-Car transfer across the placenta played a major role in maternal plasma L-Car reduction during pregnancy, which did not subsequently result in maternal hepatic fatty acid b-oxidation decrease.

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“…However, during the isolation and cultivation of PHTCs, the expression levels of transporters might be decreased or even lost, and PHTCs cannot proliferate and cannot form tightly connected monolayers. Besides, our previous study showed that mRNA expression levels of OCTN1/2, OCT3, and OAT4 are different between BeWo cells and PHTCs (47). Since cell models have their own limitations, to obtain more reliable results, transporter-transfected cell models, choriocarcinoma cell lines, and PHTCs were together applied in our study to better clarify placenta transfer of FTC.…”

Section: Discussionmentioning

confidence: 99%

“…MDCK-hOCT3, MDCK-hOCTN1/2, LLC-PK1-hBCRP, MDCK-hMDR1, MDCK-hMRP1/2/3, and the respective mock cells were seeded in 24-well plates at 2 ϫ 10 5 /well. Accumulation studies were carried out on day 3 according to a method created by our research team (47)(48)(49)(50). The activity of the transgenic cells mentioned above was tested by using classical substrates: MPP ϩ (10 M) for hOCT3, L-ergothioneine (3 M) for hOCTN1, d 3 -L-Car (3 M) for hOCTN2, Hoechst 33342 (10 M) for hBCRP, rhodamine 123 (5 M) for hMDR1, calcein-AM (10 M) for hMRP1/2, and CDCFDA (15 M) for hMRP3.…”

Section: Figmentioning

confidence: 99%

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

Zeng

Bai

et al. 2019

Antimicrob Agents Chemother

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Emtricitabine (FTC) is a first-line antiviral drug recommended for the treatment of AIDS during pregnancy. We hypothesized that transporters located in the placenta contribute to FTC transfer across the blood-placenta barrier. BeWo cells, cell models with stable or transient expression of transporter genes, primary human trophoblast cells (PHTCs), and small interfering RNAs (siRNAs) were applied to demonstrate which transporters were involved. FTC accumulation in BeWo cells was reduced markedly by inhibitors of equilibrative nucleoside transporters (ENTs), concentrative nucleoside transporters (CNTs), organic cation transporters (OCTs), and organic cation/carnitine transporter 1 (OCTN1) and increased by inhibitors of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs). ENT1, CNT1, OCTN1, MRP1/2/3, and BCRP, but not ENT2, CNT3, OCTN2, or multidrug resistance protein 1 (MDR1), were found to transport FTC. FTC accumulation in PHTCs was decreased significantly by inhibitors of ENTs and OCTN1. These results suggest that ENT1, CNT1, and OCTN1 probably contribute to FTC uptake from maternal circulation to trophoblasts and that ENT1, CNT1, and MRP1 are likely involved in FTC transport between trophoblasts and fetal blood, whereas BCRP and MRP1/2/3 facilitate FTC transport from trophoblasts to maternal circulation. Coexistence of tenofovir or efavirenz with FTC in the cell medium did not influence FTC accumulation in BeWo cells or PHTCs.

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Multiple drug transporters mediate the placental transport of sulpiride

Cited by 32 publications

References 44 publications

Multiple organic cation transporters contribute to the renal transport of sulpiride

Multiple organic cation transporters contribute to the renal transport of sulpiride

Maternal Plasma l-Carnitine Reduction During Pregnancy Is Mainly Attributed to OCTN2-Mediated Placental Uptake and Does Not Result in Maternal Hepatic Fatty Acid β-Oxidation Decline

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

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