Abolition of valproate-derived choleresis in the Mrp2 transporter-deficient rat

Wright, A. W. E. and Dickinson, R. G. (2004) Abolition of valproate-derived choleresis in the Mrp2 transporter-deficient rat. Journal of Pharmacology And Experimental Therapeutics, 310 2: 584-588.


Author Wright, A. W. E.
Dickinson, R. G.
Title Abolition of valproate-derived choleresis in the Mrp2 transporter-deficient rat
Journal name Journal of Pharmacology And Experimental Therapeutics  (ERA 2012 Listed)    (ERA 2010 Rank A)   Check publisher's open access policy
Publication date 2004
Sub-type Article
DOI 10.1124/jpet.103.064220
Volume number 310
Issue number 2
ISSN 0022-3565
Start page 584
End page 588
Total pages 5
Editor S. J. Enna
Place of publication Bethesda, U.S.A.
Publisher American Society for Pharmacology & Experimental Therapeutics
Collection year 2004
Language eng
Subject C1
320504 Toxicology (incl. Clinical Toxicology)
730199 Clinical health not specific to particular organs, diseases and conditions
Abstract 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.
Keyword Pharmacology & Pharmacy
Conjugated Hyperbilirubinemia
Beta-oxidation
Protein-3 Mrp3
Mutant Rats
Acid
Disposition
Metabolites
Excretion
Humans
Monkey
Q-Index Code C1
Additional Notes A study demonstrating the physiological consequences of deficiency of a key drug conjugate transporter in the liver.

 
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