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Cellular Uptake of Levocetirizine by Organic Anion Transporter 4
Saki Noguchi1, Tomohiro Nishimura1, Saya Mukaida1
1Faculty of Pharmacy, Keio University, Minato-ku 105-8512, Tokyo, Japan.
Abstract:
The pharmacokinetics of cetirizine, a nonsedating antihistamine, is profoundly affected by transporter-mediated membrane transport in the kidney. In this study, we aimed to investigate the transport mechanism of levocetirizine, the pharmacologically active enantiomer of cetirizine, via human organic anion transporter 4 (OAT4) expressed in the apical membrane of renal proximal tubules and the basal plasma membrane of placental syncytiotrophoblasts. In cells expressing human OAT4 under the control of tetracycline, levocetirizine uptake was increased by tetracycline treatment. On the other hand, OAT4 expression did not facilitate efflux of preloaded levocetirizine from the cells, either in the presence or absence of extracellular Cl-. The OAT4-mediated levocetirizine uptake was concentration-dependent with a Km of 38 μM. The uptake rate of levocetirizine via OAT4 was approximately twice that of racemic cetirizine, indicating stereoselective uptake of levocetirizine. On the other hand, OAT4-mediated [3H]dehydroepiandrosterone sulfate uptake was inhibited by dextrocetirizine and levocetirizine. Overall, our findings indicate that OAT4 mediates levocetirizine uptake but is unlikely to mediate the efflux.
Insights
Human organic anion transporter 4 (OAT4) facilitates the uptake of levocetirizine, the active form of cetirizine, in the kidneys. This transporter shows stereoselective uptake, preferring levocetirizine over racemic cetirizine.
Area of Science:
- Pharmacology
- Renal Physiology
- Drug Transport
Background:
- Cetirizine's pharmacokinetics are influenced by kidney transporters.
- Levocetirizine is the active enantiomer of cetirizine.
- Organic anion transporter 4 (OAT4) is present in renal proximal tubules and placental syncytiotrophoblasts.
Purpose of the Study:
- To investigate the transport mechanism of levocetirizine by human OAT4.
- To determine if OAT4 mediates levocetirizine uptake and efflux.
- To assess the stereoselectivity of OAT4 for levocetirizine.
Main Methods:
- OAT4-expressing cells were treated with tetracycline to induce transporter expression.
- Levocetirizine uptake and efflux assays were performed.
- Inhibition studies using dextrocetirizine and OAT4 substrate [3H]dehydroepiandrosterone sulfate were conducted.
Main Results:
- Tetracycline treatment increased levocetirizine uptake in OAT4-expressing cells.
- OAT4 did not facilitate levocetirizine efflux.
- OAT4-mediated levocetirizine uptake showed stereoselectivity, with a K m of 38 μM.
- Levocetirizine and dextrocetirizine inhibited OAT4-mediated [3H]dehydroepiandrosterone sulfate uptake.
Conclusions:
- OAT4 mediates the uptake of levocetirizine in a stereoselective manner.
- OAT4 is unlikely to be involved in the efflux of levocetirizine.
- These findings elucidate the renal transport mechanism of levocetirizine.