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Rapid CommunicationShort Communication

Recommendation to Exclude Bile-Duct-Cannulated Rats with Hyperbilirubinemia for Proper Conduct of Biliary Drug Excretion Studies

Koji Kato, Yoshitaka Hasegawa, Katsuya Iwata, Takuya Ichikawa, Tohru Yahara, Satoshi Tsuji, Masayuki Sugiura and Jun-ichi Yamaguchi
Drug Metabolism and Disposition August 2016, 44 (8) 1180-1183; DOI: https://doi.org/10.1124/dmd.116.070532
Koji Kato
Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan
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Yoshitaka Hasegawa
Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan
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Katsuya Iwata
Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan
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Takuya Ichikawa
Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan
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Tohru Yahara
Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan
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Satoshi Tsuji
Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan
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Masayuki Sugiura
Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan
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Jun-ichi Yamaguchi
Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan
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Abstract

Hyperbilirubinemia (HB) is sometimes encountered following bile-duct cannulation in rats. It possibly originates from the reduced functioning of multidrug resistance-associated protein 2 (Mrp2) and subsequent adaptive alterations in the expression of Mrp3 and the organic anion transporting polypeptides (Oatps). Our aim was to clarify the importance of excluding bile-duct-cannulated (BDC) rats with HB for proper conduct of drug excretion studies. We detected HB [serum total bilirubin concentration (TBIL) ≥0.20 mg/dl] in 16% of all BDC rats prepared. The serum activities of aspartate aminotransferase, alanine aminotransferase, leucine aminopeptidase, and alkaline phosphatase were within the respective normal ranges in the BDC rats with mild HB (TBIL, 0.20–0.79 mg/dl), indicating the absence of hepatic failure. In the pharmacokinetics of pravastatin, an Oatps/Mrp2 probe drug in the BDC rats, the apparent volume of distribution and the clearance were smaller in the mild HB group as compared with the normal group, suggesting the reduction of apparent hepatic uptake and hepatobiliary elimination. The biliary excretion (percentage of dose) was significantly reduced by 54%, suggesting that the biliary efflux activity via Mrp2 was reduced to a greater extent relative to metabolic activity in hepatocytes. The serum γ-glutamyltransferase (GGT) activity correlated with TBIL and inversely correlated with biliary excretion of pravastatin, a finding which could serve as a clue to uncover the regulatory system involving cooperation between GGT and Mrp2. In conclusion, BDC rats with HB, however mild, should be excluded from drug excretion studies to avoid the risk of underestimation of the biliary excretion of drugs.

Footnotes

    • Received March 23, 2016.
    • Accepted May 18, 2016.
  • dx.doi.org/10.1124/dmd.116.070532.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (8)
Drug Metabolism and Disposition
Vol. 44, Issue 8
1 Aug 2016
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Rapid CommunicationShort Communication

Impact of Hyperbilirubinemia Caused by Bile-Duct Cannulation

Koji Kato, Yoshitaka Hasegawa, Katsuya Iwata, Takuya Ichikawa, Tohru Yahara, Satoshi Tsuji, Masayuki Sugiura and Jun-ichi Yamaguchi
Drug Metabolism and Disposition August 1, 2016, 44 (8) 1180-1183; DOI: https://doi.org/10.1124/dmd.116.070532

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Rapid CommunicationShort Communication

Impact of Hyperbilirubinemia Caused by Bile-Duct Cannulation

Koji Kato, Yoshitaka Hasegawa, Katsuya Iwata, Takuya Ichikawa, Tohru Yahara, Satoshi Tsuji, Masayuki Sugiura and Jun-ichi Yamaguchi
Drug Metabolism and Disposition August 1, 2016, 44 (8) 1180-1183; DOI: https://doi.org/10.1124/dmd.116.070532
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