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Identification and Quantification of MIDD0301 Metabolites
M S Rashid Roni1, Nicolas M Zahn1, Brandon N Mikulsky2
1Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States.
Current Drug Metabolism
|December 3, 2021
Summary
MIDD0301, an asthma drug candidate, shows minimal metabolism and distributes well in the lungs. Its pharmacokinetic profile indicates a half-life of 4-6 hours after oral or IP administration.
Area of Science:
- Pharmacology
- Drug Metabolism
- Respiratory Medicine
Background:
- MIDD0301 is an investigational oral drug targeting GABAA receptors on airway smooth muscle and immune cells for asthma treatment.
- Understanding its metabolic fate and pharmacokinetic properties is crucial for clinical development.
Purpose of the Study:
- To identify and quantify metabolites of MIDD0301 in vitro and in vivo.
- To determine the pharmacokinetics of MIDD0301 following oral, intraperitoneal (IP), and intravenous (IV) administration.
Main Methods:
- Metabolite identification and quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
- In vitro metabolism studies with liver and kidney microsomes/S9 fractions.
- Pharmacokinetic analysis in blood, lung, and brain after various administration routes.
- Imaging mass spectrometry to visualize lung distribution.
Main Results:
- MIDD0301 demonstrated stability in liver and kidney microsomes.
- Phase II metabolism was observed, forming glucuronide and glucoside conjugates, with varying profiles depending on administration route.
- Low brain penetration was observed across all administration routes.
- Orally administered MIDD0301 showed uniform distribution within the lung parenchyma.
- Drug half-life ranged from 1-2 hours (IV) to 4-6 hours (oral, IP).
Conclusions:
- MIDD0301 undergoes limited Phase I metabolism and moderate Phase II metabolism.
- The drug exhibits favorable lung distribution and a moderate half-life, suggesting potential for asthma therapy.
