OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition

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 OATP1B1*1A (wild type) with a Michaelis–Menten constant of ~13 µmol/l, and that its transport was reduced by ~50% in cells expressing OATP1B1*5 (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 OATP1B1*5, 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 & Therapeutics (2012); 92 5, 642–650. doi: 10.1038/clpt.2012.106