Abolition of valproate-derived choleresis in the Mrp2 transporter-deficient rat.
Valproic acid (VPA) is a major therapeutic agent in the treatment of epilepsy and other neurological disorders. It is metabolized in humans and rats primarily along two pathways: direct glucuronidation to yield the acyl glucuronide (VPA-G) and beta-oxidation. We have shown much earlier in the Sprague-Dawley rat that i.v. administration of sodium valproate (NaVPA) caused a marked choleresis (mean of 3.3 times basal bile flow after doses of 150 mg/kg), ascribed to the passive osmotic flow of bile water following excretion of VPA-G across the canalicular membrane. Active biliary pumping of anionic drug conjugates across the canalicular membrane is now believed to be attributable to transporter proteins, in particular Mrp2, which is deficient in the TR(-) (a mutant Wistar) rat. In the present study, normal Wistar and Mrp2-deficient TR(-) rats were dosed i.v. with NaVPA at 150 mg/kg. In the Wistar rats, there was a peak choleretic effect of about 3.2 times basal bile flow, occurring at about 30 to 45 min postdose (as seen previously with Sprague-Dawley rats). In TR(-) rats given the same i.v. dose, there was no evidence of postdose choleresis. The choleresis was correlated with the excretion of VPA-G into bile. In Wistar rats, 62.8 +/- 7.7% of the NaVPA dose was excreted in bile as VPA-G, whereas in TR(-) rats, only 2.0 +/- 0.6% of the same dose was excreted as VPA-G in bile (with partial compensatory excretion of VPA-G in urine). This study underlines the functional (bile flow) consequences of biliary transport of xenobiotic conjugated metabolites.
Wright
Andrew W E
AW
Centre for Studies in Drug Disposition, Clinical Sciences Building, University of Queensland, Royal Brisbane Hospital, Brisbane, Queensland, Australia. awright@ccs.uq.edu.au
Dickinson
Ronald G
RG
D000818:Animals; D001646:Bile / Q000187:drug effects* / Q000378:metabolism*; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency* / Q000235:genetics; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology*
D002756:Cholagogues and Choleretics; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014635:Valproic Acid; C000715087:ABCC2 protein, human