Organic anion transporter 3 interacts selectively with lipophilic beta-lactam antibiotics.

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Wolman AT, Gionfriddo MR, Heindel GA, Mukhija P, Witkowski S, Bommareddy A, Vanwert AL

Organic anion transporter 3 interacts selectively with lipophilic beta-lactam antibiotics.

Drug Metab Dispos. 2013 Apr;41(4):791-800. doi: 10.1124/dmd.112.049569. Epub 2013 Jan 23.

PubMed ID

23344796 [ View in PubMed

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Abstract

Transporters are major determinants of the disposition of xenobiotics and endogenous chemicals in the body. Organic anion transporter 3 (Oat3) functions in the kidney and brain to remove metabolic waste, toxins, and drugs, and thus transports diverse chemicals. Some beta-lactam antibiotics interact with Oat3, and penicillin G exhibits a strong dependence on Oat3 for renal elimination. However, over 80 beta-lactams exist, and many have not been assessed for an interaction with Oat3. Moreover, beta-lactams continue to receive U.S. Food and Drug Administration approval. This study identified new beta-lactam-Oat3 interactions, provided a head-to-head comparison with Oat1, and characterized the physicochemical determinants of affinity for Oat3. Cells expressing mouse Oat3 (mOat3) and Oat1 (mOat1), and human OAT3 (hOAT3) were used to test inhibitors, and high-performance liquid chromatography (HPLC) was used to measure transport. Of 26 beta-lactams tested, 12 were clear inhibitors of Oat3, and 14 exhibited poor interactions. Inhibitors exhibited a nearly identical rank-order of potency against mOat3 and hOAT3. Oat1 demonstrated a poor interaction with most beta-lactams. The majority of Oat3 inhibitors were substrates, and there were clear physicochemical differences between inhibitors and noninhibitors. That is, inhibitors had nearly 40% fewer hydrogen bond donors (P < 0.001), a lower total polar surface area (P < 0.05), and greater lipophilicity (LogP of inhibitors, +1.41; noninhibitors, -1.54; P < 0.001). Pharmacophore mapping revealed a prohibitive hydrogen bond donor group in noninhibitors adjacent to a hydrophobic moiety that was important for binding to Oat3. These findings indicate that Oat3 recognizes lipophilic beta-lactams more readily. Moreover, this study has potential implications for designing beta-lactams to avoid renal accumulation or brain efflux via Oat3.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Cloxacillin	Solute carrier family 22 member 8	Protein	Humans	No	Substrate Inhibitor	Details