Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?
Tolvaptan is a vasopressin V(2)-receptor antagonist that has shown promise in treating Autosomal Dominant Polycystic Kidney Disease (ADPKD). Tolvaptan was, however, associated with liver injury in some ADPKD patients. Inhibition of bile acid transporters may be contributing factors to drug-induced liver injury. In this study, the ability of tolvaptan and two metabolites, DM-4103 and DM-4107, to inhibit human hepatic transporters (NTCP, BSEP, MRP2, MRP3, and MRP4) and bile acid transport in sandwich-cultured human hepatocytes (SCHH) was explored. IC(50) values were determined for tolvaptan, DM-4103 and DM-4107 inhibition of NTCP (∼41.5, 16.3, and 95.6 μM, respectively), BSEP (31.6, 4.15, and 119 μM, respectively), MRP2 (>50, ∼51.0, and >200 μM, respectively), MRP3 (>50, ∼44.6, and 61.2 μM, respectively), and MRP4 (>50, 4.26, and 37.9 μM, respectively). At the therapeutic dose of tolvaptan (90 mg), DM-4103 exhibited a C(max)/IC(50) value >0.1 for NTCP, BSEP, MRP2, MRP3, and MRP4. Tolvaptan accumulation in SCHH was extensive and not sodium-dependent; intracellular concentrations were ∼500 μM after a 10-min incubation duration with tolvaptan (15 μM). The biliary clearance of taurocholic acid (TCA) decreased by 43% when SCHH were co-incubated with tolvaptan (15 μM) and TCA (2.5 μM). When tolvaptan (15 μM) was co-incubated with 2.5 μM of chenodeoxycholic acid, taurochenodeoxycholic acid, or glycochenodeoxycholic acid in separate studies, the cellular accumulation of these bile acids increased by 1.30-, 1.68-, and 2.16-fold, respectively. Based on these data, inhibition of hepatic bile acid transport may be one of the biological mechanisms underlying tolvaptan-associated liver injury in patients with ADPKD.
*Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; kbrouwer@unc.edu.
Jason R
JR
Slizgi
*Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599;
Yang
Y
Lu
Qualyst Transporter Solutions, Durham, North Carolina 27713; and.
Kenneth R
KR
Brouwer
Qualyst Transporter Solutions, Durham, North Carolina 27713; and.
Robert L
RL
St Claire
Qualyst Transporter Solutions, Durham, North Carolina 27713; and.
Kimberly M
KM
Freeman
Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Maryland 20850.
Maxwell
M
Pan
Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Maryland 20850.
William J
WJ
Brock
*Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; kbrouwer@unc.edu.
Kim L R
KL
Brouwer
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000633:toxicity*; D001552:Benzazepines / Q000378:metabolism / Q000633:toxicity*; D016466:CHO Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D003412:Cricetulus; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy; D013656:Taurocholic Acid / Q000378:metabolism; D000077602:Tolvaptan
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013656:Taurocholic Acid; D000077602:Tolvaptan; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human; C037643:bile acid binding proteins; C114462:multidrug resistance-associated protein 3
bile acids; drug-induced liver injury; hepatic transporters