title: In vitro OATP1B1 and OATP1B3 inhibition is associated with observations of benign clinical unconjugated hyperbilirubinemia.
abstract: 1.  Transient benign unconjugated hyperbilirubinemia has been observed clinically with several drugs including indinavir, cyclosporine, and rifamycin SV. Genome-wide association studies have shown significant association of OATP1B1 and UGT1A1 with elevations of unconjugated bilirubin, and OATP1B1 inhibition data correlated with clinical unconjugated hyperbilirubinemia for several compounds. 2.  In this study, inhibition of OATP1B3 and UGT1A1, in addition to OATP1B1, was explored to determine whether one measure offers value over the other as a potential prospective tool to predict unconjugated hyperbilirubinemia. OATP1B1 and OATP1B3-mediated transport of bilirubin was confirmed and inhibition was determined for atazanavir, rifampicin, indinavir, amprenavir, cyclosporine, rifamycin SV and saquinavir. To investigate the intrinsic inhibition by the drugs, both in vivo Fi (fraction of intrinsic inhibition) and R-value (estimated maximum in vivo inhibition) for OATP1B1, OATP1B3 and UGT1A1 were calculated. 3.  The results indicated that in vivo Fi values >0.2 or R-values >1.5 for OATP1B1 or OATP1B3, but not UGT1A1, are associated with previously reported clinical cases of drug-induced unconjugated hyperbilirubinemia. 4.  In conclusion, inhibition of OATP1B1 and/or OATP1B3 along with predicted human pharmacokinetic data could be used pre-clinically to predict potential drug-induced benign unconjugated hyperbilirubinemia in the clinic.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Division of Development Sciences, Global Pharmaceutical Research and Development, AbbVie, Inc. , North Chicago, IL 60064 , USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Chiou
authors.forename: Sonia M
authors.initials: SM
authors.lastname: de Morais
authors.forename: Ryota
authors.initials: R
authors.lastname: Kikuchi
authors.forename: Richard L
authors.initials: RL
authors.lastname: Voorman
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.forename: Daniel A J
authors.initials: DA
authors.lastname: Bow
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology*; D000069446:Atazanavir Sulfate; D001663:Bilirubin / Q000378:metabolism; D002219:Carbamates; D016572:Cyclosporine; D005663:Furans; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006932:Hyperbilirubinemia / Q000378:metabolism*; D066298:In Vitro Techniques; D019469:Indinavir; D027381:Liver-Specific Organic Anion Transporter 1; D009842:Oligopeptides; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines; D012293:Rifampin; D012294:Rifamycins; D019258:Saquinavir; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides; D000099148:UGT1A1 Enzyme
chemical_list: D018501:Antirheumatic Agents; D000069446:Atazanavir Sulfate; D001663:Bilirubin; D002219:Carbamates; D016572:Cyclosporine; D005663:Furans; D014453:Glucuronosyltransferase; D017320:HIV Protease Inhibitors; D019469:Indinavir; D027381:Liver-Specific Organic Anion Transporter 1; D009842:Oligopeptides; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011725:Pyridines; D012293:Rifampin; D012294:Rifamycins; D019258:Saquinavir; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides; D000099148:UGT1A1 Enzyme; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C095108:amprenavir; C023808:rifamycin SV