OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition
- 19 September 2012
- journal article
- clinical trial
- Published by Wiley in Clinical Pharmacology & Therapeutics
- Vol. 92 (5), 642-650
- https://doi.org/10.1038/clpt.2012.106
Abstract
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.2012.106Keywords
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