Altered Pharmacokinetics of Cimetidine Caused by Down-regulation of Renal Rat Organic Cation Transporter 2 (rOCT2) after Liver Ischemia-Reperfusion Injury

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Author(s)

    • IKEMURA Kenji
    • College of Pharmacy, Kinjo Gakuin University|Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine
    • NAKAGAWA Erika
    • Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine
    • KURATA Tomohiko
    • Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine
    • IWAMOTO Takuya
    • Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine|Department of Pharmacy, Mie University Hospital
    • OKUDA Masahiro
    • Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine|Department of Pharmacy, Mie University Hospital

Abstract

  The renal tubular secretion of cationic drugs is dominated by basolateral organic cation transporter 2 (rOCT2/SLC22A2) and luminal multidrug and toxin extrusion 1 (rMATE1/SLC47A1). Little is known about the variation in the expression of these renal transporters after liver ischemia-reperfusion (I/R) injury. Here, we examined the pharmacokinetics of a cationic drug, cimetidine, and renal rOCT2 and rMATE1 levels as well as their regulation after liver I/R. Rats were subjected to 60 min of liver ischemia followed by 12 h of reperfusion. The antioxidant Trolox<sup>®</sup> was administered intravenously 5 min before reperfusion. The systemic and tubular secretory clearances of cimetidine (78% and 55%) as well as renal rOCT2 and rMATE1 levels (67% and 61%) in I/R rats were decreased compared with those in sham-operated rats, respectively. However, the renal tissue-to-plasma concentration ratio but not the renal tissue-to-urine clearance ratio of cimetidine was decreased after liver I/R. Moreover, Trolox prevented the decreases in renal rOCT2 levels and systemic clearance of cimetidine after liver I/R. These results demonstrate that liver I/R decreases the tubular secretion of cimetidine, mainly because of the decreased rOCT2 level in the kidney, and that oxidative stress should be responsible in part for decreased renal rOCT2 after liver I/R injury.<br>

Journal

  • Drug Metabolism and Pharmacokinetics

    Drug Metabolism and Pharmacokinetics 28(6), 504-509, 2013

    The Japanese Society for the Study of Xenobiotics

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