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Cefditoren, a β-lactam antibiotic, is widely used in respiratory tract and skin infections in the clinic. This study was aimed at investigating the mechanism underlying hepatic uptake of cefditoren in rats and humans. Cmax of cefditoren plasma exposure was increased (0.80 ± 0.06 to 1.02 ± 0.16 μg mL−1) when co-administrated with rifampicin. Extraction ratio of cefditoren was decreased (34.70% ± 4.61% to 18.30% ± 2.89%) by combining with rifampicin in perfused rat livers in situ. Uptake of cefditoren by rat liver slices was temperature-dependent and significantly inhibited by Oatp modulators, such as ibuprofen, digoxin, cyclosporin A and glycyrrhizic acid, but not by tetraethylammonium or p-aminohippurate. Uptake of cefditoren in hOATP1B1- and hOATP2B1-human embryonic kidney (HEK) 293 cells indicated a saturable process with a Km of 189.7 ± 60.4 μmol L−1 and 122.7 ± 37.37 μmol L−1, respectively. Sartans inhibited the transport of cefditoren in hOATP1B1- and hOATP2B1-HEK293 cells. Moreover, cefditoren could increase the gene and protein expression levels of Oatp1a1 in rat liver, while Oatp1a4 and Oatp1b2 were unchanged. These results indicated that OATP1B1 and OATP2B1 are involved in hepatic uptake of cefditoren in humans, and multiple Oatps (Oatp1a1, Oatp1a4 and Oatp1b2) might participate in this process in rats. In addition, cefditoren could prompt the up-regulation of Oatp1a1 expression. In the clinic, additional attention should be paid to the alternative exposure of cefditoren when co-administrated with sartans or other drugs that are substrates or inhibitors of OATP1B1 and/or OATP2B1.

Liver uptake of cefditoren is mediated by OATP1B1 and OATP2B1 in humans and Oatp1a1, Oatp1a4, and Oatp1b2 in rats