Inhibition of Hepatobiliary Transporters by A Novel Kinase Inhibitor Contributes to Hepatotoxicity in Beagle Dogs

Title:Inhibition of Hepatobiliary Transporters by A Novel Kinase Inhibitor Contributes to Hepatotoxicity in Beagle Dogs

Volume: 7 Issue: 1

Author(s): John Scott Daniels, Yurong Lai, Sarah South, Po-Chang Chiang, Daniel Walker, Bo Feng, Rouchelle Mireles, Laurence O. Whiteley, Jeremy W. Mckenzie, Jeffrey Stevens, Robert Mourey, David Anderson and John W. Davis II

Affiliation:

Keywords: Acute toxicity, metabolism, transporters, xenobiotic.

Abstract: PF-022 (1) is a novel polycyclic benzothiophene kinase inhibitor selective for mitogen-activated protein kinase-activated protein kinase 2 (MK2). Compound 1 emerged as an inhibitor bearing submicromolar potency against MK2 (IC₅₀ 5 nM) and demonstrated projected human pharmacokinetics sufficient for oral dosing. However, following a single, oral administration of 1 to beagle dogs, animals experienced an acute liver injury characterized by increases in biomarkers associated with hepatotoxicity; particularly noteworthy was the reversible elevation in bile salts and total bilirubin. Accompanying this observation was an ADME appraisal which included hepatic bioactivation of 1 in multiple species and the in vitro inhibition of P-glycoprotein (P-gp; IC₅₀ 21 μM). Simply attenuating the bioactivation via structural modification proved ineffective in improving the in vivo tolerability of this polycyclic scaffold. Hence, disruption of hepatobiliary transporters by the compound series was hypothesized as the likely mechanism contributing to the acute hepatotoxicity. Indeed, closer in vitro examination employing transporter gene overexpressing MDCK cell lines and membrane vesicles revealed potent compound-dependent inhibition of human multi-drug resistance-associated protein 2 (MRP2/ABCC2; IC₅₀ 38 μM) and bile salt export pump (BSEP/ABCB11; IC₅₀ 10 μM), two crucial hepatobiliary transport proteins accountable for bilirubin and bile salt homeostasis, respectively. Subsequent introduction of pK_a-altering modifications to a second generation compound PF029 proved successful in reducing its affinity for these key efflux transporters (MRP2 IC₅₀ >>80 μM; BSEP IC₅₀ > 70 μM; P-gp > 90 μM), consequently mitigating this overt organ toxicity in dogs.

Cite this article as:

Daniels Scott John, Lai Yurong, South Sarah, Chiang Po-Chang, Walker Daniel, Feng Bo, Mireles Rouchelle, Whiteley O. Laurence, Mckenzie W. Jeremy, Stevens Jeffrey, Mourey Robert, Anderson David and II W. Davis John, Inhibition of Hepatobiliary Transporters by A Novel Kinase Inhibitor Contributes to Hepatotoxicity in Beagle Dogs, Drug Metabolism Letters 2013; 7 (1) . https://dx.doi.org/10.2174/18723128112066660018