OATP1B1 polymorphism as a determinant of erythromycin disposition.
Clin Pharmacol Ther
; 92(5): 642-50, 2012 Nov.
Article
en En
| MEDLINE
| ID: mdl-22990751
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Eritromicina
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Transportadores de Anión Orgánico
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Transportadores de Anión Orgánico Sodio-Independiente
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Antibacterianos
Límite:
Adult
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Aged
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Aged80
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Clin Pharmacol Ther
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos