OATP1B1 polymorphism as a determinant of erythromycin disposition.

C S Lancaster, G H Bruun, C J Peer, T S Mikkelsen, T J Corydon, A A Gibson, S Hu, S J Orwick, R H J Mathijssen, W D Figg, S D Baker, A Sparreboom

Clinical pharmacology and therapeutics 2012 Nov

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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.

Citation

C S Lancaster, G H Bruun, C J Peer, T S Mikkelsen, T J Corydon, A A Gibson, S Hu, S J Orwick, R H J Mathijssen, W D Figg, S D Baker, A Sparreboom. OATP1B1 polymorphism as a determinant of erythromycin disposition. Clinical pharmacology and therapeutics. 2012 Nov;92(5):642-50