Previous studies have demonstrated that the pharmacokinetic profile of erythromycin, a probe for CYP3A4 activity, is affected by inhibitors or inducers of hepatic solute carriers. We hypothesized that these interactions are mediated by OATP1B1 (gene symbol, SLCO1B1), a polypeptide expressed on the basolateral surface of hepatocytes. Using stably transfected Flp-In T-Rex293 cells, erythromycin was found to be a substrate for OATP1B11A (wild type) with a MichaelisMenten constant of ∼13mol/l, and that its transport was reduced by ∼50% in cells expressing OATP1B15 (V174A). Deficiency of the ortholog transporter Oatp1b2 in mice was associated with a 52% decrease in the metabolic rate of erythromycin (P = 0.000043). In line with these observations, in humans the c.521T>C variant in SLCO1B1 (rs4149056), encoding OATP1B15, was associated with a decline in erythromycin metabolism (P = 0.0072). These results suggest that impairment of OATP1B1 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.,
Clinical Pharmacology and Therapeutics
Department of Medical Oncology

Lancaster, C.S, Bruun, G.H, Peer, C.J, Mikkelsen, T.S, Corydon, T.J, Gibson, A.A, … Sparreboom, A. (2012). OATP1B1 polymorphism as a determinant of erythromycin disposition. Clinical Pharmacology and Therapeutics, 92(5), 642–650. doi:10.1038/clpt.2012.106