Article pubs.acs.org/crt
Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals Michael D. Aleo,*,§,# Falgun Shah,∥,@,# Kan He,⊥ Paul D. Bonin,‡ and A. David Rodrigues† †
Medicinal Sciences, ADME CoE, Pfizer Inc., Groton, Connecticut 06340, United States Medicinal Sciences, Discovery Sciences, Pfizer Inc., Groton, Connecticut 06340, United States § Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut 06340, United States ∥ Computational Sciences, Pfizer Inc., Cambridge, Massachusetts 02139, United States ⊥ Biotranex LLC, Monmouth Junction, New Jersey 08852, United States ‡
S Supporting Information *
ABSTRACT: The role of bile salt export protein (BSEP) inhibition in drug-induced liver injury (DILI) has been investigated widely, while inhibition of the canalicular multidrug resistant protein 3 (MDR3) has received less attention. This transporter plays a pivotal role in secretion of phospholipids into bile and functions coordinately with BSEP to mediate the formation of bile acid-containing biliary micelles. Therefore, inhibition of MDR3 in human hepatocytes was examined across 125 drugs (70 of Most-DILI-concern and 55 of No-DILI-concern). Of these tested, 41% of Most-DILI-concern and 47% of No-DILI-concern drugs had MDR3 IC50 values of 8.4 or ApKa1 = “NaN” and BpKa1 < 6.4 or BpKa1 = “NaN”; zwitterions (Zwit), ApKa ≤ 8.4 and BpKb1 ≥ 6.4. A logical regression model was developed to correlate each physicochemical property with MDR3 inhibition using JMP12.0 (SAS Institute Inc., Cary, NC). The logistic regression method was used to estimate the probability of a compound being free from MDR3 inhibition as a function of each molecular property (cLogP, cPFLogD, log10MW, log10PSA, pKa, and pKb). For cyanocobalamin, our internal cPFLogD model failed to generate a numerical value, and hence, the model was built using the 124 remaining compounds. The statistical significance of each property model was then assessed by calculating the significance probability (or p value) for the χ2 test and R2 value, quantifying relationships between these properties and MDR3 inhibition as described previously.21 A p value of
