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Microbial models of mammalian metabolism O-demethylations of papaverine
Abstract:
1. Papaverine is converted to its 4'-, 6- and 7-desmethyl metabolites when incubated with hepatic microsomal preparations from phenobarbital-induced rats. The 7-desmethyl compound was predominantly formed in these studes. When incubated with guinea-pig microsomal preparations, papaverine was converted to its 6- and 4'-desmethyl metabolites in approximately equal amounts. 2. The O-demethylation of papaverine was studied with sixty micro-organisms. Ten organisms (including Aspergillus Cunninghamella and Streptomyces species) were found to actively metabolize this drug in a manner similar to that of mammals. 3. A strain of Aspergillus alliaceus was used to produce gram quantitites of the mammalian metabolite, 6-desmethylpapaverine. Preparative amounts of 4'-desmethylpapaverine, a major mammalian metabolite of papaverine in vivo, was produced with a strain of Cunninghamella echinulata.
Insights
Papaverine metabolism was studied in rats, guinea pigs, and microorganisms. Certain microbes, like Aspergillus and Cunninghamella, mimic mammalian papaverine O-demethylation, producing key metabolites.
Area of Science:
- Pharmacology
- Microbiology
- Drug Metabolism
Background:
- Papaverine is an opium alkaloid used medically.
- Understanding papaverine's metabolic pathways is crucial for drug development and efficacy.
- Hepatic microsomal enzymes and microorganisms play roles in drug biotransformation.
Purpose of the Study:
- To investigate the O-demethylation of papaverine by mammalian liver microsomes.
- To identify microorganisms capable of metabolizing papaverine similarly to mammals.
- To produce specific papaverine metabolites using microbial biotransformation.
Main Methods:
- Incubation of papaverine with hepatic microsomal preparations from phenobarbital-induced rats and guinea pigs.
- Screening of sixty microbial strains for papaverine O-demethylation activity.
- Large-scale cultivation of specific microbial strains (Aspergillus alliaceus, Cunninghamella echinulata) for metabolite production.
Main Results:
- Rat hepatic microsomes predominantly formed 7-desmethylpapaverine.
- Guinea pig hepatic microsomes produced 6- and 4'-desmethylpapaverine in equal amounts.
- Ten microbial strains, including Aspergillus, Cunninghamella, and Streptomyces, exhibited mammalian-like papaverine metabolism.
- Aspergillus alliaceus produced 6-desmethylpapaverine, and Cunninghamella echinulata produced 4'-desmethylpapaverine in preparative quantities.
Conclusions:
- Mammalian O-demethylation of papaverine varies between species (rat vs. guinea pig).
- Certain microorganisms effectively mimic mammalian papaverine metabolism.
- Microbial biotransformation offers a viable method for producing specific papaverine metabolites like 6- and 4'-desmethylpapaverine.