title: Systems pharmacology modeling of drug-induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters.
abstract: Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model-predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir-mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug-induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin.
authors.affiliation: DILIsym Services Inc, Research Triangle Park, North Carolina, USA.
authors.forename: K
authors.initials: K
authors.lastname: Yang
authors.affiliation: DILIsym Services Inc, Research Triangle Park, North Carolina, USA.|University of North Carolina Institute for Drug Safety Sciences, The Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: C
authors.initials: C
authors.lastname: Battista
authors.affiliation: DILIsym Services Inc, Research Triangle Park, North Carolina, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Woodhead
authors.affiliation: ADME Transporters, Drug Safety and Metabolism, Innovative Medicines and Early Development, AstraZeneca, Cambridge, United Kingdom.
authors.forename: S H
authors.initials: SH
authors.lastname: Stahl
authors.affiliation: Drug Safety and Metabolism, AstraZeneca R&D, Waltham, Massachusetts, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Mettetal
authors.affiliation: University of North Carolina Institute for Drug Safety Sciences, The Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Watkins
authors.affiliation: DILIsym Services Inc, Research Triangle Park, North Carolina, USA.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Siler
authors.affiliation: DILIsym Services Inc, Research Triangle Park, North Carolina, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Howell
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000097:blood / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000473:pathology; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D019469:Indinavir / Q000493:pharmacokinetics / Q000633:toxicity; D008099:Liver / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019888:Nelfinavir / Q000493:pharmacokinetics / Q000633:toxicity; D010599:Pharmacokinetics; D051381:Rats; D011911:Rats, Gunn; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors; D049490:Systems Biology
chemical_list: D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D019707:Receptors, Chemokine; D019469:Indinavir; D019888:Nelfinavir; D001663:Bilirubin