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.

dx.doi.org/10.1038/clpt.2012.106, hdl.handle.net/1765/59963
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