J Cory Kalvass1, Candace L Graff, Gary M Pollack. 1. Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Abstract
PURPOSE: A subpopulation of the CF-1 mouse strain (approximately 25%) lacks P-gp expression, and consequently, increased brain penetration of many substrates is observed in these animals. Mice lacking the mdr1a gene represent an important research tool to study the potential effects of P-gp on CNS substrate disposition. METHODS: Adult CF-1 mice were used in all experiments. Loperamide-induced antinociception was determined by the hotplate latency test at 0.25, 2, and 4 h post-dose. At the conclusion of the pharmacodynamic experiment(s), trunk blood and brain tissue were collected and analyzed by high-performance liquid chromatography-mass spectrometry (LC-MS/MS). Mice were also genotyped for their mdrla status via RT-PCR. RESULTS: All mice with three consecutive effects of maximum hotplate latency (60 s) showed considerable opioid-like behavior in addition to antinociception. Mice without three consecutive effects of maximum hotplate latency (< or = 30 s) showed no opioid-like behavior. The loperamide brain-to-serum ratio in mice identified as P-gp-deficient was 65-fold higher compared to the P-gp-competent animals (10.1 +/- 1.0 vs. 0.155 +/- 0.018). All animals identified as phenotypically P-gp-competent based on the hotplate assay evidenced the mdrla(+/+) genotype. CONCLUSION: This assay appears to offer a rapid and unambiguous measure via a relatively non-invasive, simple technique to identify P-gp status in the CF-1 subpopulation of mice.
PURPOSE: A subpopulation of the CF-1 mouse strain (approximately 25%) lacks P-gp expression, and consequently, increased brain penetration of many substrates is observed in these animals. Mice lacking the mdr1a gene represent an important research tool to study the potential effects of P-gp on CNS substrate disposition. METHODS: Adult CF-1 mice were used in all experiments. Loperamide-induced antinociception was determined by the hotplate latency test at 0.25, 2, and 4 h post-dose. At the conclusion of the pharmacodynamic experiment(s), trunk blood and brain tissue were collected and analyzed by high-performance liquid chromatography-mass spectrometry (LC-MS/MS). Mice were also genotyped for their mdrla status via RT-PCR. RESULTS: All mice with three consecutive effects of maximum hotplate latency (60 s) showed considerable opioid-like behavior in addition to antinociception. Mice without three consecutive effects of maximum hotplate latency (< or = 30 s) showed no opioid-like behavior. The loperamide brain-to-serum ratio in mice identified as P-gp-deficient was 65-fold higher compared to the P-gp-competent animals (10.1 +/- 1.0 vs. 0.155 +/- 0.018). All animals identified as phenotypically P-gp-competent based on the hotplate assay evidenced the mdrla(+/+) genotype. CONCLUSION: This assay appears to offer a rapid and unambiguous measure via a relatively non-invasive, simple technique to identify P-gp status in the CF-1 subpopulation of mice.
Authors: D R Umbenhauer; G R Lankas; T R Pippert; L D Wise; M E Cartwright; S J Hall; C M Beare Journal: Toxicol Appl Pharmacol Date: 1997-09 Impact factor: 4.219
Authors: P Borst; A H Schinkel; J J Smit; E Wagenaar; L Van Deemter; A J Smith; E W Eijdems; F Baas; G J Zaman Journal: Pharmacol Ther Date: 1993-11 Impact factor: 12.310
Authors: Kunal S Taskar; Xinning Yang; Sibylle Neuhoff; Mitesh Patel; Kenta Yoshida; Mary F Paine; Kim L R Brouwer; Xiaoyan Chu; Yuichi Sugiyama; Jack Cook; Joseph W Polli; Imad Hanna; Yurong Lai; Maciej Zamek-Gliszczynski Journal: Clin Pharmacol Ther Date: 2022-06-22 Impact factor: 6.903
Authors: Hazem E Hassan; Susan L Mercer; Christopher W Cunningham; Andrew Coop; Natalie D Eddington Journal: Int J Pharm Date: 2009-04-05 Impact factor: 5.875