Solvent-based formulations for intravenous mouse pharmacokinetic studies: tolerability and recommended solvent dose limits.

Abstract

1. Modern high-throughput small molecule drug discovery requires rapid screening of the pharmacokinetic parameters of multiple candidate molecules in parallel. The mouse is often used for such screening, as are solvent-based intravenous formulations. Despite this, the intravenous toxicity of many commonly used solvents is unknown. The purpose of this investigation is to establish recommended no-observed-effect level (NOEL) and maximum tolerated dose (MTD) for several commonly used intravenous solvents in the CD-1 mouse. 2. The acute tolerability of polyethylene glycol 400, N-methylpyrrolidone, dimethyl sulfoxide, ethanol, dimethylacetamide and propylene glycol was established, along with combinations of polyethylene glycol 400 and/or ethanol and DMSO. Based on these data, an acute NOEL and recommended MTD is reported for each solvent or solvent combination. 3. These data can guide the use of these solvents to support single-dose intravenous pharmacokinetic studies in mice. By establishing a defined dose tolerability range for the most commonly used intravenous solvents, undue pain and distress in animals can be avoided while maximizing the generation of critical pharmacokinetic data for project teams.

• Authors: Evan A Thackaberry, Xiaojing Wang, Michelle Schweiger, Kirsten Messick, Nicole Valle, Brian Dean, Amy Sambrone, Terri Bowman, Minli Xie
• Journal: Xenobiotica; the fate of foreign compounds in biological systems (Xenobiotica) Vol. 44 Issue 3 Pg. 235-41 (Mar 2014) ISSN: 1366-5928 [Electronic] England
• PMID: 24138296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Pyrrolidinones
• Solvents
• Ethanol
• Polyethylene Glycols
• Propylene Glycol
• dimethylacetamide
• N-methylpyrrolidone
• Dimethyl Sulfoxide

Topics

• Acetamides (administration & dosage, adverse effects)
• Administration, Intravenous
• Animals
• Dimethyl Sulfoxide (administration & dosage, adverse effects)
• Dose-Response Relationship, Drug
• Ethanol (administration & dosage, adverse effects)
• Female
• High-Throughput Screening Assays (methods)
• Maximum Tolerated Dose
• Mice
• No-Observed-Adverse-Effect Level
• Pharmacokinetics
• Polyethylene Glycols (administration & dosage, adverse effects)
• Propylene Glycol (administration & dosage, adverse effects)
• Pyrrolidinones (administration & dosage, adverse effects)
• Solvents (administration & dosage, adverse effects)