One of the greatest challenges with successful pharmaceutical treatments of central nervous system (CNS) diseases is the delivery of drugs into their target sites with appropriate concentrations. For example, the physically tight blood-brain barrier (BBB) effectively blocks compounds from penetrating into the brain, also by the action of metabolizing enzymes and efflux transport mechanisms. However, many endogenous compounds, including both smaller compounds and macromolecules, like amino acids, sugars, vitamins, nucleosides, hormones, steroids, and electrolytes, have their peculiar internalization routes across the BBB. These delivery mechanisms, namely carrier-mediated transport and receptor-mediated transcytosis have been utilized to some extent in brain-targeted drug development. The incomplete knowledge of the BBB and the smaller than a desirable number of chemical tools have hindered the development of successful brain-targeted pharmaceutics. This review discusses the recent advancements achieved in the field from the point of medicinal chemistry view and discusses how brain drug delivery can be improved in the future.

• Klíčová slova
• Brain-blood barrier, Carrier-mediated transport, Drug delivery, Prodrug approach, Receptor-mediated transport,
• MeSH
• biofarmacie * MeSH
• biologický transport MeSH
• hematoencefalická bariéra metabolismus   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• nemoci centrálního nervového systému * MeSH
• systémy cílené aplikace léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

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 Km of 4.21 mM and Vmax 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.

• MeSH
• ABC transportéry metabolismus   MeSH
• biologický transport fyziologie   MeSH
• buněčné linie MeSH
• buňky MDCK MeSH
• krysa rodu Rattus MeSH
• lamivudin metabolismus   MeSH
• lidé MeSH
• P-glykoproteiny metabolismus   MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• psi MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• ABCC2 protein, human MeSH Prohlížeč
• lamivudin MeSH
• P-glykoproteiny MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH