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.