title: Recommendation to Exclude Bile-Duct-Cannulated Rats with Hyperbilirubinemia for Proper Conduct of Biliary Drug Excretion Studies.
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.
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan ko-katou@so.taisho.co.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Kato
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Iwata
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ichikawa
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yahara
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sugiura
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Yamaguchi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001652:Bile Ducts / Q000378:metabolism*; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002404:Catheterization / Q000009:adverse effects*; D065669:Hepatobiliary Elimination; D006932:Hyperbilirubinemia / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000378:metabolism; D017035:Pravastatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D015415:Biomarkers; D027361:Organic Anion Transporters; D017035:Pravastatin; D001663:Bilirubin