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OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition
Author(s) -
Lancaster C S,
Bruun G H,
Peer C J,
Mikkelsen T S,
Corydon T J,
Gibson A A,
Hu S,
Orwick S J,
Mathijssen R H J,
Figg W D,
Baker S D,
Sparreboom A
Publication year - 2012
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2012.106
Subject(s) - disposition , erythromycin , polymorphism (computer science) , genetics , biology , pharmacology , medicine , psychology , genotype , antibiotics , gene , social psychology
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