Abstract

The effects of hepatic uptake and efflux transporters on erythromycin (ERY) disposition and metabolism were examined by comparing results from rat hepatic microsomes, freshly isolated hepatocytes, and in vivo studies. Uptake studies carried out in freshly isolated rat hepatocytes showed that ERY and its metabolite (N-demethyl-ERY) are substrates of Oatp1a4 and Oatp1b2. Whereas rifampin and GG918 [GF120918: N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine] exerted minimal effects on metabolism in microsomes, rifampin (2.5 μM) and GG918 (0.5 μM) significantly decreased and increased ERY metabolism in hepatocytes, respectively. Concentration-time course studies further demonstrated that, compared with the intracellular N-demethyl-ERY control area under the curve (AUC) (0.795 ± 0.057 μM · min), a decreased AUC (0.513 ± 0.028 μM · min, p < 0.005) was observed when ERY was coincubated with rifampin, and an increased AUC (2.14 ± 0.21 μM · min, p < 0.05) was found when GG918 was present. The results of the i.v. bolus studies showed that, compared with the ERY clearance of the controls (47.2 ± 12.5 ml/min/kg for the rifampin group and 42.1 ± 5.7 for the GG918 group), a decreased blood clearance, 29.8 ± 6.1 ml/min/kg (p < 0.05) and 21.7 ± 9.0 ml/min/kg (p < 0.01), was observed when rifampin or GG918, respectively, was coadministered. When either inhibitor was codosed with ERY, volume of distribution at steady state was unchanged, but t_1/2 and mean residence time significantly increased compared with the controls. Hepatic uptake and efflux transporters modulate intracellular concentrations of ERY, thereby affecting metabolism. The interplay of transporters and enzymes must be considered in evaluating potential drug-drug interactions.