title: OATP1B1 polymorphism as a determinant of erythromycin disposition.
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.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Lancaster
authors.forename: G H
authors.initials: GH
authors.lastname: Bruun
authors.forename: C J
authors.initials: CJ
authors.lastname: Peer
authors.forename: T S
authors.initials: TS
authors.lastname: Mikkelsen
authors.forename: T J
authors.initials: TJ
authors.lastname: Corydon
authors.forename: A A
authors.initials: AA
authors.lastname: Gibson
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.forename: S J
authors.initials: SJ
authors.lastname: Orwick
authors.forename: R H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004917:Erythromycin / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D011110:Polymorphism, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C498887:Slco1b2 protein, mouse; D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human