OATP1B1 polymorphism as a determinant of erythromycin disposition.

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Lancaster CS, Bruun GH, Peer CJ, Mikkelsen TS, Corydon TJ, Gibson AA, Hu S, Orwick SJ, Mathijssen RH, Figg WD, Baker SD, Sparreboom A

OATP1B1 polymorphism as a determinant of erythromycin disposition.

Clin Pharmacol Ther. 2012 Nov;92(5):642-50. doi: 10.1038/clpt.2012.106. Epub 2012 Sep 19.

PubMed ID

22990751 [ View in PubMed

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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 micromol/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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Erythromycin	Solute carrier organic anion transporter family member 1B1	Protein	Humans	No	Substrate Inhibitor	Details