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-REx 293 cells, erythromycin was found to be a substrate for OATP1B1*1A (wildtype) with a Km of ~13 µM, and 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 genotype-dosage dependent decline in erythromycin metabolism (P = 0.0072). These results suggest that impaired OATP1B1 function can alter erythromycin metabolism independently of changes in CYP3A4 activity.

Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

“…The amount of exhaled CO2 metabolite of hydroxyurea was measured using a breath test as described elsewhere (16,33). Briefly, the mice received a tail vein injection of 50 mg/kg hydroxyurea containing [ 14 C]hydroxyurea (1 Ci/100 g; American Radiolabeled Chemicals) in saline.…”

“…In humans, the OATP1B family of transporters consists of OATP1B1 and OATP1B3 transporters that are encoded by SLCO1B genes (10). Predominantly expressed in the liver on the sinusoidal membrane of hepatocytes (15), these transporters are important for regulating the elimination of endogenous substrates such as bilirubin and can impact the disposition of drugs such as methotrexate and various statins (14,16,19,21,27). The rodent ortholog of the human OATP1B transporters is Oatp1b2 (4).…”

PharmGKB summary

“…Genetic variants in ABCB1 (P-gp) and ABCC2 (MRP2) have been reported to affect the transport and clearance of erythromycin [20, 21]. Patients with both the 2677GG (rs2032582) and 3435CC (rs1045642) diplotypes in ABCB1 reportedly had higher maximum concentrations of azithromycin compared to patients with the 2677TT/3435TT diplotypes [16].…”

“…SLCO1B1 transports erythromycin into the liver, and the SLCO1B1*5 (rs4149056) variant reportedly results in a 50% reduction in erythromycin transport, explaining about 10% of the variability in erythromycin demethylation as assessed with the erythromycin breath test [21]. Additionally, variation in the SLCO1B3 gene has been associated with altered accumulation of erythromycin in the liver, with a variant at the 334 locus (rs4149117) increasing transporter activity and increasing erythromycin uptake [20].…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…Evidence of this cooperative functionality is observed concerning the hepatic clearance of erythromycin, a commonly used probe to assess CYP3A function (Rivory et al, 2001). Erythromycin uptake into hepatocytes is mediated by OATPs (Sun et al, 2010;Lancaster et al, 2012). OATPs facilitate the uptake of erythromycin from the portal vein and into hepatocytes where metabolism by CYP3A occurs (Franke et al, 2011).…”