Purpose: To identify the rat hepatic basolateral transporters involved in the hepatic uptake of beta-lactam antibiotics using nafcillin as a model beta-lactam antibiotic that undergoes extensive biliary excretion.
Materials and methods: Uptake by isolated rat hepatocytes and Xenopus laevis oocytes expressing organic anion transporting peptides (Oatp1, 2, and 4) and organic anion transporter (OAT2) was evaluated.
Results: Nafcillin uptake by isolated rat hepatocytes was saturable with the Km of 210 microM and was significantly inhibited by anionic compounds (estrone-3-sulfate and sulfobromophthalein), but not by cationic compounds (tetraethylammonium and 1-methyl-4-phenylpyridinium). In an in vitro uptake study by Xenopus oocytes expressing hepatic basolateral membrane transporters, nafcillin was transported by multiple Oatps with Km values of 4120 microM (Oatp1/Oatp1a1), 198 microM (Oatp2/Oatp1a4), and 1,570 microM (Oatp4/Oatp1b2), though it was not transported by hOAT2. Comparison of affinity and analysis by the relative activity factor method indicated that Oatp2 is the predominant contributor to the hepatic uptake of nafcillin. Cefadroxil, cefazolin, cefmetazole, cefoperazone, cefsulodin, and cephalexin, though not cefotaxime or ceftriaxone, were also substrates of Oatp2.
Conclusion: These findings suggest that Oatp2 plays a key role in the hepatic uptake of nafcillin and most other beta-lactam antibiotics in rats.