Comparison of bidirectional lamivudine and zidovudine transport using MDCK, MDCK–MDR1, and Caco-2 cell monolayers

Souza, Jacqueline de; Benet, Leslie Z.; Huang, Yong; Storpirtis, Sílvia

doi:10.1002/jps.21744

Cited by 62 publications

(44 citation statements)

References 18 publications

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“…These findings clearly confirm TDF as a substrate of ABCB1 transporter as suggested recently [17,18]. Based on our findings, TDF seems to be a substrate as strong as colchicine, model substrate often used for in-vitro assays [27], topotecan [22] or other antiretrovirals including zidovudine [28], abacavir [29] or lopinavir [30].…”

Section: Discussionsupporting

confidence: 87%

Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta

Neumanova

Červený²,

Čečková³

et al. 2014

Aids

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Section: Discussionsupporting

confidence: 87%

Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta

Neumanova

Červený²,

Čečková³

et al. 2014

Aids

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“…Based on the lack of interaction of lamivudine with a potent P-gp inhibitor (GG 918), the authors concluded that P-gp does not significantly affect the transport of lamivudine (39). Correspondingly, we did not observe any P-gp-accelerated transport of lamivudine (8 nM) across the MDCK-MDR1 monolayers, confirming the lack of relevant P-gp involvement in lamivudine transport.…”

Section: Discussionsupporting

confidence: 63%

“…Interaction of lamivudine with P-gp was evaluated by de Souza et al (39), using a transport assay with P-gp-expressing monolayers. Based on the lack of interaction of lamivudine with a potent P-gp inhibitor (GG 918), the authors concluded that P-gp does not significantly affect the transport of lamivudine (39).…”

Section: Discussionmentioning

confidence: 99%

Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine

Čečková

Reznicek

Ptackova

et al. 2016

Antimicrob Agents Chemother

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Lamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employed in vitro accumulation and transport experiments on MDCK cells overexpressing drug efflux transporters, in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparent K m of 4.21 mM and V max of 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent with in vitro transport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport.

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“…This results in decreased absorption and bioavailability of low permeability drugs that are sensitive to changes in gastrointestinal (GI) motility and transit time 10, 11. Lamivudine is a highly soluble and well‐absorbed drug with an absolute bioavailability of 86% in adults5; however, there are conflicting reports as to whether lamivudine is a low or high permeability drug,12 with the results of an in vitro Caco‐2 study characterizing its permeability as moderate 13. Although the lamivudine oral solution itself does not contain sorbitol, if the permeability of lamivudine is in the low‐to‐moderate range, it may be susceptible to an absorption‐based interaction with sorbitol present in coadministered antiretroviral drugs, such as abacavir oral solution and nevirapine suspension, as well as other chronically administered liquid formulations of prescription or over‐the‐counter medications used to treat comorbidities.…”

mentioning

confidence: 99%

Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in Adults: An Open‐Label, Randomized Study

Adkison¹,

Wolstenholme

Lou

et al. 2017

Clin Pharma and Therapeutics

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In children aged ≤4 years, the relative bioavailability of lamivudine oral solution was 37% lower than that of a tablet formulation. An open‐label, four‐way crossover study was conducted in healthy adults to evaluate the effect of sorbitol, a common liquid excipient, on the pharmacokinetics of lamivudine oral solution (ClinicalTrials.gov identifier, NCT02634073). Sixteen subjects were randomized to one of four sequences consisting of four doses of lamivudine 300 mg (10 mg/mL) alone or with sorbitol 3.2, 10.2, or 13.4 g. Sorbitol 3.2, 10.2, and 13.4 g decreased lamivudine maximum concentration (C max) by 28%, 52%, and 55% and area under the concentration–time curve from time 0 to 24 h (AUC0‐24) by 20%, 39%, and 44%, respectively. Three subjects (19%) reported five nonserious adverse events (one drug‐related). The dose‐dependent effects of sorbitol on lamivudine C max and AUC0‐24 reveal an absorption‐based interaction that may decrease lamivudine exposure in patients coadministered sorbitol‐containing medicines.

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Comparison of bidirectional lamivudine and zidovudine transport using MDCK, MDCK–MDR1, and Caco-2 cell monolayers

Cited by 62 publications

References 18 publications

Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta

Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta

Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine

Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in Adults: An Open‐Label, Randomized Study

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