 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Apr 08, 2013 |
| Title |
Minor compensatory changes in SAGE Mdr1a (P-gp), Bcrp, and Mrp2 knockout rats do not detract from their utility in the study of transporter-mediated pharmacokinetics. |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by array
|
| Summary |
Mdr1a-, Bcrp-, and Mrp2-knockout rats are a more practical species for ADME studies than murine models and previously demonstrated expected alterations in pharmacokinetics of various probe substrates. At present, gene expression and pathology changes were systematically studied in small intestine, liver, kidney, and brain tissue from male SAGE Mdr1a-, Bcrp-, and Mrp2-knockout rats versus wild-type Sprague Dawley controls. Gene expression data supported the relevant knockout genotype. As expected, Mrp2-knockout rats were hyperbilirubinemic and exhibited upregulation of hepatic Mrp3. Overall, few alterations were observed within 137 ADME-relevant genes. The two most consequential changes were upregulation of intestinal carboxylesterase in Mdr1a-knockouts and catechol-O-methyltransferase in all tissues of Bcrp-knockout rats. Previously reported upregulation of hepatic Mdr1b P-glycoprotein in proprietary Wistar Mdr1a-knockout rats was not observed in the SAGE counterpart investigated herein. Relative liver and kidney weights were 22-53% higher in all three knockouts, with microscopic increases in hepatocyte size in Mdr1a- and Mrp2-knockout rats, and glomerular size in Bcrp- and Mrp2-knockouts. Increased relative weight of clearing organs is quantitatively consistent with reported increases in clearance of drugs that are not substrates of the knocked-out transporter. Overall, SAGE knockout rats demonstrated modest compensatory changes, which do not preclude their general application to study transporter-mediated pharmacokinetics. However until future studies elucidate the magnitude of functional change, caution is warranted in rare instances of extensive metabolism by catechol-O-methyltransferase in Bcrp-knockouts and intestinal carboxylesterase in Mdr1a-knockout rats, specifically for molecules with free catechol groups and esters subject to gut wall hydrolysis.
|
| |
|
| Overall design |
3 groups of knockout animals compared to wild-type male Sprague Dawley control rats. 4 animals per group. Assayed the following tissues: brain, duodenum, ileum, jejunum, kidney (cortex-anterior pole), kidney (medulla), liver. Hybridized to Affymetrix Rat Genome 230 v2 [Rat230_2] arrays.
|
| |
|
| Contributor(s) |
Zamek-Gliszczynski MJ, Goldstein KM, Paulman A, Baker TK, Ryan TP |
| Citation(s) |
23569176 |
| Submission date |
Mar 07, 2013 |
| Last update date |
Jul 31, 2017 |
| Contact name |
Keith M Goldstein |
| E-mail(s) |
goldsteinkm@lilly.com
|
| Organization name |
Eli Lilly & Co.
|
| Department |
Investigative Toxicology
|
| Lab |
Keith Goldstein
|
| Street address |
Lilly Corporate Center
|
| City |
Indianapolis |
| State/province |
IN |
| ZIP/Postal code |
46285 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL1355 |
[Rat230_2] Affymetrix Rat Genome 230 2.0 Array |
|
| Samples (111)
|
|
| Relations |
| BioProject |
PRJNA192623 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE44962_RAW.tar |
323.6 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
|
|
|
|
 |
Less...
More...