Speeding Up Drug Metabolism Screening
A new study published in the journal Analytical Chemistry presents a drug metabolism strategy based on microsome mesoporous organosilica nanoreactors coupled with high performance liquid chromatography–mass spectrometry (HPLC–MS) to screen for potential drug toxicity.
Photo Credit: FrankRamspott/Getty Images
A major hurdle in the drug development process is the clinical testing stage, where up to 40% of drugs fail because of previously unidentified toxicity.1 There is therefore the need for low-cost high-throughput methods to identify toxicity at the early stages of drug development. A new study published in the journal Analytical Chemistry presents a drug metabolism strategy based on microsome mesoporous organosilica nanoreactors coupled with high performance liquid chromatography–mass spectrometry (HPLC–MS) to screen for potential drug toxicity.1 According to the paper, human liver microsomes are commonly used in drug metabolism studies as they contain an enriched source of human metabolic enzymes (including cytochrome P450 and uridine diphosphogluconosyl transferase [UGT]) that account for almost 80% of the metabolism of drugs.
Multi-well plate assay systems have been previously developed to allow the simultaneous metabolism of various drug candidates, but are limited in their approach. Corresponding author Baohong Liu from Fudan University in Shanghai, China, told The Column: “Many in vitro metabolic reactions either suffer from limitations such as slow kinetics and low conversion efficiency, or differ from the in vivo processes. To address the problem, a rapid and accurate in vitro drug metabolism strategy has been developed based on the design of a biomimetic nanoreactor composed of amino-functionalized mesoporous organosilica and microsomes.”
The authors immobilized hydrophobic and negatively charged microsomes containing metabolic enzymes onto amino-functionalized periodic mesoporous organosilica to form “NH2-PMO microsome nanoreactors”. The nanoreactors were added to solutions containing nifedipine or testosterone and incubated. NADPH was subsequently added to initiate oxidation of the drugs. The drug molecules and their metabolites were then extracted and analyzed using HPLC–MS. The authors found that the metabolic reaction with nanoreactors was much more efficient than the in-solution reaction. For example, for nifedipine a conversion of ∼75% was achieved with the nanoreactors, while in solution it was 15%.
Liu told The Column: “Such a biomimetic micro-/nano-reactor can provide a suitable environment to confine enzymes and substrates with high local concentrations, as well as to maintain their catalytic activities for rapid and highly effective drug metabolic reactions. Combination of the nanoreactors with HPLC–MS provides a simple, rapid and accurate strategy for in vitro study of drug metabolites.” - B.D.
Reference
1. X. Fang et al., Anal. Chem.86(21), 10870–10876 (2014).
This article is from The Column. The full issue can be found here>>
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