Assessment of Macrolide Transport Using PAMPA, Caco-2 and MDCKII-hMDR1 Assays

The transport of commercially available macrolide antibiotics erythromycin, clarithromycin, roxithromycin, azithromycin, and telithromycin was studied by PAMPA, a model of passive diffusion, and by two models of active transport, Caco-2 and MDCKII-hMDR1. An involvement of efflux pump P-glycoprotein (P-gp) in macrolide transport was also examined. Generally, in Caco-2 and MDCKII-hMDR1 assays without P-gp inhibition, a significantly lower apparent permeability (P app ) in apical-to-basolateral (AB) than basolateral-to-apical (BA) direction was observed [efflux ratio, P app ratio(BA/AB) > 4.2]. Upon P-gp inhibition, P app (AB) was increased and P app (BA) was decreased. The observed P app values, their efflux ratios, as well as a significant decrease in efflux ratios caused by P-gp inhibition (> 50 %) qualify all tested macrolides as P-gp substrates. Results obtained with PAMPA suggest that this assay is not a method of choice for screening of macrolide permeability due to the lack of P-gp efflux pump and/or other transporters potentially involved in macrolide transport.