Apparent Differences in Mechanisms of Harmol Sulfate Biliary Excretion in Mice and Rats

• Published in: Drug metabolism and disposition Vol. 36; no. 11; pp. 2156 - 2158
• Main Authors: Zamek-Gliszczynski, Maciej J., Hoffmaster, Keith A., Nezasa, Ken-ichi, Brouwer, Kim L. R.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.11.2008
• Subjects: Acridines - metabolism; Animals; Biliary Tract - chemistry; Biliary Tract - drug effects; Biliary Tract - secretion; Biological and medical sciences; Harmine - analogs & derivatives; Harmine - chemistry; Harmine - pharmacology; Harmine - secretion; Liver - chemistry; Liver - drug effects; Liver - secretion; Male; Medical sciences; Mice; Mice, Inbred C57BL; Pharmacology. Drug treatments; Rats; Rats, Wistar; Species Specificity; Structure-Activity Relationship; Tetrahydroisoquinolines - metabolism; Biliary tract; Vertebrata; Excretion; Mammalia; Rat; Mouse; Digestive system; Animal; Rodentia; Pharmacokinetics; Mechanism of action; Sulfates
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.108.022053

Previous experiments demonstrated that the biliary excretion of harmol sulfate (HS) was mediated by breast cancer resistance protein (Bcrp) and not by multidrug resistance-associated protein (Mrp)2 or P-glycoprotein in mice. However, recent reports suggested that species differences in hepatic canalicular transport mechanisms for a given substrate exist between mice and rats. In the present study, biliary excretion of HS was examined in perfused livers from mice and rats in the absence or presence of the P-glycoprotein and Bcrp inhibitor N -(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). As expected, in mouse liver perfusions, the biliary excretion of HS was decreased ∼3.5-fold by GF120918, consistent with previous reports of Bcrp-mediated HS biliary excretion. However, despite sufficient hepatic unbound concentrations of GF120918 to achieve extensive inhibition of Bcrp, the biliary excretion of HS was not decreased significantly in wild-type (50 ± 12 versus 41 ± 6%) or TR - (18 ± 2 versus 16 ± 3%) Wistar rats. In summary, biliary excretion of HS was mediated by a GF120918-sensitive mechanism in mice, previously elucidated as Bcrp. In contrast, the pathway responsible for HS biliary excretion in rats was not impaired by GF120918. Thus, transport mechanism(s) responsible for harmol sulfate biliary excretion appear to differ between mice and rats.