Assessment of Amino Acid/Drug Transporters for Renal Transport of [18F]Fluciclovine (anti-[18F]FACBC) in Vitro. ↗
Ono M, Baden A, Okudaira H, Kobayashi M, Kawai K, Oka S, Yoshimura H.
Inte granskat av ActiQs. Detta är en automatiskt skapad sammanställning.
Vad undersöktes?
- Hur undersöktes det?
- In this study, we investigated the involvement of AATs and drug transporters in renal [18F]fluciclovine reuptake.
- Vilka undersöktes?
- Ingen uppgift i sammanställningen
- Vilken ämnesform?
- [14C]Fluciclovine (trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid)
- Vilken mängd användes?
- Ingen uppgift i sammanställningen
- Hur länge pågick studien?
- Ingen uppgift i sammanställningen
Studieuppgifterna återges som originalcitat. Uppgifter som saknas här kan finnas i originalutdraget.
Vad kom studien fram till?
Författarna rapporterar att i en in vitro-modell av njurens proximala tubuli dämpade l-treonin transporten av [14C]fluciclovine och att upptaget via de testade läkemedelstransportörerna inte skilde sig signifikant från kontroller. De drar slutsatsen att system ASC-transportörer kan bidra delvis till återupptag av [18F]fluciclovine; studien undersökte även hämning av vissa läkemedelstransportörer vid millimolära koncentrationer.
Vad behöver resultatet vägas mot?
Studien var in vitro och använde LLC-PK1-monolager som modell för proximala njurtubuli samt vesiklar/celler som uttryckte läkemedelstransportörer; resultaten fastställer inte transportens betydelse hos människor. Underlaget omfattar endast utvalda artikelstycken; någon samlad bedömning kan inte göras.
Läs de originalstycken som sammanställningen bygger på
Abstract[18F]Fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid; anti-[18F]FACBC), a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs) with high affinity (Km: 97–230 μM). However, the mechanism underlying urinary excretion is unknown. In this study, we investigated the involvement of AATs and drug transporters in renal [18F]fluciclovine reuptake. [14C]Fluciclovine (trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid) was used because of its long half-life. The involvement of AATs in [14C]fluciclovine transport was measured by apical-to-basal transport using an LLC-PK1 monolayer as model for renal proximal tubules. The contribution of drug transporters herein was assessed using vesicles/cells expressing the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) , organic cation transporter 2 (OCT2), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporting polypeptide 1B3 (OATP1B3). The apical-to-basal transport of [14C]fluciclovine was attenuated by l-threonine, the substrate for system alanine-serine-cysteine (ASC) AATs. [14C]Fluciclovine uptake by drug transporter-expressing vesicles/cells was not significantly different from that of control vesicles/cells. Fluciclovine inhibited P-gp, MRP4, OAT1, OCT2, and OATP1B1 (IC50 > 2.95 mM). Therefore, system ASC AATs may be partly involved in the renal reuptake of [18F]fluciclovine. Further, given that [18F]fluciclovine is recognized as an inhibitor with millimolar affinity for the tested drug transporters, slow urinary excretion of [18F]fluciclovine may be mediated by system ASC AATs, but not by drug transporters.
3. DiscussionWe conducted a series of studies to assess the involvement of AATs and drug transporters in the distribution of [14C]fluciclovine in vitro, thereby specifically focusing on renal reuptake. The apical-to-basal transport of [14C]fluciclovine in the LLC-PK1 monolayer model was inhibited by Thr, a substrate representative for system ASC AATs [,]. Furthermore, control vesicles/cells and ABC/SLC drug transporter-expressing vesicles/cells showed no significant differences in drug transporter-mediated [14C]fluciclovine uptake. Fluciclovine at millimolar concentrations inhibited the uptake of specific substrates by some of the drug transporters tested. Our study suggests that the slow urinary excretion of [18F]fluciclovine is partly mediated by system ASC AATs, which serve as high-affinity transporters for [18F]fluciclovine uptake/efflux, but that the contribution of drug transporters to [18F]fluciclovine distribution is negligible compared to that of AATs.
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