Role of Hepatic Transporters in the Disposition and Hepatotoxicity of a HER2 Tyrosine Kinase Inhibitor CP-724,714

Abstract

CP-724,714, a potent and selective orally active HER2 tyrosine kinase inhibitor, was discontinued from clinical development due to unexpected hepatotoxicity in cancer patients. Based on the clinical manifestation of the toxicity, CP-724,714 likely exerted its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. The direct cytotoxic effect, hepatobiliary disposition of CP-724,714, and its inhibition of active canalicular transport of bile constituents were evaluated in established human hepatocyte models and in vitro transporter systems. CP-724,714 exhibited direct cytotoxicity using human hepatocyte imaging assay technology with mitochondria identified as a candidate organelle for its off-target toxicity. Additionally, CP-724,714 was rapidly taken up into human hepatocytes, partially via an active transport process, with an uptake clearance approximately fourfold higher than efflux clearance. The major human hepatic uptake transporter, OATP1B1, and efflux transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein, were involved in hepatobiliary clearance of CP-724,714. Furthermore, CP-724,714 displayed a concentration-dependent inhibition of cholyl-lysyl fluorescein and taurocholate (TC) efflux into canaliculi in cryopreserved and fresh cultured human hepatocytes, respectively. Likewise, CP-724,714 inhibited TC transport in membrane vesicles expressing human bile salt export pump with an IC(50) of 16 microM. Finally, CP-724,714 inhibited the major efflux transporter in bile canaliculi, MDR1, with an IC(50) of approximately 28 microM. These results suggest that inhibition of hepatic efflux transporters contributed to hepatic accumulation of drug and bile constituents leading to hepatocellular injury and hepatobiliary cholestasis. This study provides likely explanations for clinically observed adverse liver effects of CP-724,714.

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

“…Other well-studied anticancer drugs handled by OATP1B1 and OATP1B3 are rapamycin (sirolimus) and SN-38 (7-ethyl-10-hydroxycamptothecin, an active metabolite of irinotecan) (21,(24)(25)(26)(27). Additionally, OATP1B1 transports CP-724,714 (a Her2 tyrosine kinase inhibitor), cis-diamminechloro-cholylglycinate-platinum(II) (a bile-acid cisplatin derivative), and gimatecan (a camptothecin analog) (28)(29)(30). Imatinib, used for leukemia therapy, is reported to be transported by OATP1A2 and OATP1B3 (31,32).…”

Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity

“…The interruption of bile salt efflux has been reported as a cause for cholestatic liver damage (Pauli-Magnus and Meier, 2006), and inhibition of the bile salt export pump transporter by lapatinib and its phenol metabolite M1 has recently been investigated (C. MacLauchlin, G. Bowers, R. Brown, S. Castellino, G. Generaux, R. Groselclose, R. Miller, D. Newall, L. Webster, and J. Polli, unpublished observations). Feng et al (2009) suggested a combination of direct cytotoxicity to mitochondria and inhibition of bile salt efflux to explain the clinical hepatoxicity observed by a structurally similar tyrosine kinase inhibitor. In relation to both mechanisms of toxicity, the authors cite the role uptake and efflux transporters play in controlling intracellular hepatic concentrations.…”

“…In the case of the tyrosine kinase inhibitor E- 2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide 714), direct mitochondrial toxicity and inhibition of bile salt efflux are reported to contribute to hepatotoxicity (Feng et al, 2009). In a recent study, a clinical pharmacogenetic investigation of patients taking lapatinib reported a significant association between the major histocompatability complex HLA-DQA1*02:01 and ALT elevation (Spraggs et al, 2011).…”

Interindividual Variability in Hepatic Expression of the Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2): Quantification by Liquid Chromatography/Tandem Mass Spectrometry

“…Factors affecting this pathway can have a significant impact on the hepatic concentration, clearance, and toxicity of drugs or their metabolites (Stieger et al, 2000;Kostrubsky et al, 2001;Endres et al, 2006Endres et al, , 2009Feng et al, 2009;Ohtsuki et al, 2012). In humans, the measurement of the in vivo biliary clearance of drugs is difficult unless the intestine is catheterized (Bergman et al, 2010).…”