Experience
These are some of the recent and more interesting challenges that QPS overcame and contribute to our sponsor's goals. Come back and browse this page as it will be updated regularly.
Correlating Site of Action with Biological Activity
Drugs Cross the Placental Barrier
Correlating Site of Action with Biological Activity
QPS was involved in localization of a biologic in specific regions of brain involved in the pathophysiology of a neural degenerative disease. The biologic interferes (i.e. silents) with a specific messenger RNA (mRNA) and prevents synthesis of the defective protein found in the brain of patients with the degenerative disease. After a forty-eight hour continuous infusion of the radioactive biologic into the putamen using a proprietary technology, specific areas with high concentrations of the radiolabeled biologic were identified using microautoradiography (MARG). Effects of the biologic were determined by measuring the amount of mRNA in the identified brain areas compared to untreated control brain areas using quantitative real time reverse transcription-polymerase chain reaction (qRT-PCR). The results indicated that a forty-eight hour infusion of the biologic into the specific region of the brain known to be involved in the degenerative disease did not produce a significant suppressive effect on the mRNA. Combining MARG and biological effect is a powerful research tool to investigate the site of action and possible therapeutic benefits of a chemical or biologic drug.
QPS was involved in a project to improve the oral bioavailability of an anti-infective with promising in vitro activity but had limited water solubility and plasma and tissue concentrations below the target concentrations after oral and subcutaneous (SC) administrations. Using a tiered approach to identify enabling formulations, starting with primarily aqueous solutions and suspensions with pH adjustment, primarily aqueous solutions with solubilizing agents, primarily co-solvents (± other solubilizers) and finally, lipid based (± solubilizers). In a study completed at QPS, aqueous-based vehicles containing surfactants and cyclodextrins as solubilizing agents and several non-aqueous dosing vehicles were identified for in vivo comparisons. In a 14-day bid SC study, the best formulation resulted in several tissues demonstrating higher concentrations of the anti-infective than in plasma and peak and trough tissue concentrations of the compound exceeded the target concentrations.
Drugs Cross the Placental Barrier
QPS was involved in a study to evaluate the maternal and fetal distribution of an [14C-]anti-HIV drug and its metabolites using quantitative phosphor imaging of whole-body sections (QWBA) and microautoradiography (MARG) in pregnant rats at day 17 of gestation.
The QWBA results clearly showed differences in maternal and fetal tissue distributions of radioactivity. Fetal brain drug-derived radioactivity concentrations were 8.5-fold higher than maternal brain. Fetal liver concentrations were 60% higher than maternal liver. In most other fetal and maternal tissues, the concentrations in the maternal and fetal tissues were similar. However, concentrations in the fetal kidney were approximately 5-fold lower than in maternal kidney.
MARG provided a microscopic evaluation of the distribution of radioactivity in maternal and fetal tissues. The cellular distribution of the drug-derived radioactivity was different in both maternal and fetal brain and liver. Distribution in the fetal brain was more diffusely distributed and at a higher concentration than that seen in the maternal brain. The fetal brain had high amounts of labeled material throughout all regions, thus higher and possible over-exposure to the test article. The blood-brain barrier in the fetal brain at day 17 of gestation is underdeveloped and thus probably accounted for the higher amounts of radioactivity compared to the maternal brain.
Radiochromatograms of maternal and fetal brain extracts revealed that the higher concentration in fetal brain was most likely due to a higher proportion of the glucuronide metabolite and not the parent drug, whereas the proportion of parent drug was higher in the maternal brain.
