, Volume 21, Issue 10, pp 1867-1870

Use of Loperamide as a Phenotypic Probe of mdr1a Status in CF-1 Mice

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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 mdr1a 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 (≤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 mdr1a(+/+) 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.