| Abstract | The hepatobiliary disposition of thyroxine (T4) was evaluated in Groningen Yellow transport deficient (TR(-)) rats lacking functional multidrug resistance-associated protein 2 (Mrp2; Abcc2). Male Wistar and TR(-) rats were dosed orally (4 days) with phenobarbital (PB; 100 mg/kg) or DMP 904 (200 mg/kg), after which T4 homeostasis and hepatic cytochromes P450, UDP-glucuronosyltransferase, xenobiotic transporters, and T4 glucuronidation were determined. Serum concentrations of T4 were approximately 50% higher in control TR(-) rats than Wistars. PB and DMP 904 increased hepatic levels of P450s and T4-glucuronidation (T4-G), and these changes were associated with decreased serum T4 levels in both strains. In Wistar but not TR(-) rats, DMP 904 increased thyroid stimulating hormone levels twofold. Hepatobiliary clearance of T4 was determined after intravenous infusion of [(125)I]T4 to rats dosed with PB and DMP 904 (4 days). PB and DMP 904 increased plasma clearance and hepatic uptake of [(125)I]T4 equivalents in Wistar but not TR(-) rats. Total biliary clearance (Cl(bile)) was approximately 0.85 and 0.2 ml/h in Wistar and TR(-) rats, respectively, with virtually no T4-G excreted in bile in TR(-) rats. Biliary clearance of unconjugated T4 was also lower in control TR(-) rats than in Wistars, although DMP 904 increased its biliary clearance in both strains. These results suggest that Mrp2 is likely to be responsible for biliary excretion of T4-G and contributes in part to excretion of T4. Decreased biliary clearance of T4 and metabolites in TR(-) rats mitigated but did not prevent drug-induced changes in serum T4, suggesting that other factors contribute to changes in T4 homeostasis in these rats. |
| Authors | Lloyd Lecureux, Matthew Z Dieter, David M Nelson, Linda Watson, Harvey Wong, Brian Gemzik, Curtis D Klaassen, Lois D Lehman-McKeeman
(Affiliation: Discovery Toxicology, Bristol Myers Squibb Company, Princeton, New Jersey 08543, USA. Iloyd.lecureux at bms.com)
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| Journal | Toxicological sciences : an official journal of the Society of Toxicology
(Toxicol Sci)
Vol. 108
Issue 2
Pg. 482-91
(Apr 2009)
ISSN: 1096-0929 [Electronic] United States |
| PMID | 19211616
(Publication Type: Journal Article)
|
| Chemical References |
- ATP-Binding Cassette Transporters
- Abcc2 protein, rat
- Glucuronides
- RNA, Messenger
- Receptors, Thyroid Hormone
- Thyroid Hormones
- Xenobiotics
- Triiodothyronine
- Thyroxine
- Thyrotropin
|
| Topics |
- ATP-Binding Cassette Transporters
(genetics, physiology)
- Animals
- Animals, Genetically Modified
- Bile
(metabolism)
- Biliary Tract
(metabolism, pathology)
- Cell Proliferation
(drug effects)
- Chromatography, High Pressure Liquid
- Glucuronides
(metabolism)
- Homeostasis
(physiology)
- Hypothyroidism
(chemically induced, metabolism)
- Liver
(metabolism, pathology)
- Male
- Microsomes, Liver
(drug effects, metabolism)
- RNA, Messenger
(biosynthesis, genetics)
- Rats
- Rats, Wistar
- Receptors, Thyroid Hormone
(genetics)
- Thyroid Gland
(metabolism, pathology)
- Thyroid Hormones
(metabolism)
- Thyrotropin
(metabolism)
- Thyroxine
(metabolism)
- Triiodothyronine
(metabolism)
- Xenobiotics
(toxicity)
|
