Active transport of anionic and cationic drugs plays a critical role in their intestinal absorption, penetration across the blood-cerebrospinal fluid (CSF) and blood-brain barriers, and accumulation within excretory organs. In general, separate systems mediate the transport of charged organic solutes, the organic anion (OAT) and organic cation (OCT) transporter families. However, a number of drugs, e.g., the cation cimetidine, are transported by both systems. Using both Xenopus oocytes and cell lines expressing cloned drug transporters, we have examined their ability to handle several nucleoside phosphonate antiviral (NPA) drugs -- adefovir, cidofovir, and tenofovir. Of these drug transporters, only OAT1 and the ATP-driven drug pump, MRP2, transported the NPAs. OCTs 1 and 2 did not -- not surprising given the negative charge on these drugs at physiological pH. However, more unexpected was the observation that none of the NPAs were transported by the OAT3 transporters from mouse, rat, or human. Thus, it appears that the extensive accumulation these drugs in the renal proximal tubule and the associated human nephrotoxicity reflects their avid (Km's ~5 uM) transport via OAT1. In contrast to the kidney where the NPAs are well transported, the choroid plexus -- a component of the blood-CSF barrier, shows limited accumulation of NPAs. This observation may now be understood based on the very low levels of OAT1 expressed there and the resulting dependence of choroid plexus transport of anionic drugs on OAT3, which does not transport the NPAs. This conclusion has now been confirmed in the OAT3 knockout mouse that shows no change in plexus NPA transport despite nearly complete loss of the transport of mOAT3 substrates including taurocholate and estrone sulfate. This observation also indicates that other transporters, most likely the MRPs, are responsible for the limited penetration of the NPAs into the brain across the blood-brain and blood-CSF barriers.
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