Transporters, enzymes, and enalapril removal in a rat (CC531-induced) liver metastatic model.
Temporal changes in physiological spaces, protein expression of transporters and enzymes, and enalapril removal were appraised in the metastatic liver tumor model developed from male Wag/Rij rats after the intraportal injection of CC531 colon adenocarcinoma cells; sham-operated preparations received PBS. Liver tissue spaces, investigated with multiple indicator dilution technique in liver perfusion studies, were unchanged at week 3 after tumor induction. At week 4, however, the sinusoidal blood volume and albumin Disse space in tumor-bearing livers were slightly lower compared with those of shams. Increased levels of the canalicular ATP transporters, P-glycoprotein, multidrug resistance-associated protein 2 (Mrp2), and bile salt export pump (Bsep) at week 2 (P < 0.05), unchanged levels of Ntcp, Oatp1a1, Oatp1a4, and Mct2, but decreased levels of cytochrome P450 3a2 (Cyp3a2) and glutathione S-transferase (Gst4-4) at week 4 (P < 0.05) were observed in peritumor vs. sham-operated liver tissues with Western blotting. The steady-state extraction ratio of enalapril, a substrate that enters the liver rapidly via Oatp1a1 and primarily undergoes metabolism by the carboxylesterases, was unaffected by liver metastasis at week 4 regardless of its delivery via the portal vein or hepatic artery into the perfused liver preparations.
Liu
Lichuan
L
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Sun
Huadong
H
Valji
Wiqas Y
WY
Pang
K Sandy
KS
D000818:Animals; D004656:Enalapril / Q000493:pharmacokinetics*; D004798:Enzymes / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009362:Neoplasm Metastasis / Q000473:pathology / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D004798:Enzymes; D009363:Neoplasm Proteins; D004656:Enalapril