How Can P450 Enzyme Activity Be Inhibited for Slowing Drug Metabolism?

[gravenewworld]

Anyone know any good ways to inhibit the P450 enzyme in order to slow down drug metabolism? I know that cannabidiols can be used to inhibit P450, but are there any other ways?? Anyone have any good journal references (I don't have access to scifinder)? Any help would be appreciated.

-Thanks, GNW

 

[DocToxyn]

Are you looking for pharmacological inhibitors or "natural" agents? Grapefruit juice can inhibit several cyp isoforms. Are you looking to target a specific P450, if so which one? This could determine which inhibitor to use. With this info, I should be able to help.

 

[gravenewworld]

I am looking for pharmacological inhibitors. Specifically, I would like the inhibitor to stop p450(I'm not sure what specific one) from metabolising cannabinoids.

 

[DocToxyn]

I've got some more specific information regarding this, I can get it together early next week. A few words to intro the subject though. I'm assuming you are trying to prolong/extend the biological half-life of the cannabinoids by slowing down breakdown. This may work in theory however there are certain specifics to consider. P450s are part of phase I metabolism which hydroxylate the intended substrate, this is generally followed by phase II action which entails addition of bulkier groups like glucuronides or sulfides. Many P450s actually initiate bioactivation, thus creating metabolites that are more potent than the parent drug. There may be a more efficacious way to achieve your intended results. To be continued...

 

[gravenewworld]

I'm assuming you are trying to prolong/extend the biological half-life of the cannabinoids by slowing down breakdown.

Yup.


Thanks for the effort so far. Have you come across anything that says introduction of fluorine to a compound slowls metabolism? I am also curious as to what structural feature of a cannabidiol is responsible for P450 inhibition.

 

[DocToxyn]

I found a couple of good papers regarding the metabolism of active THC-related compounds. I'll give them to you and let you sift through them to find the information you specifically require. The following are PubMed abstracts since I don't know whether you have any insitutional license for these particular journals. Your library should be able to get them for you if you don't (interlibrary loan).

http://www.ncbi.nlm.nih.gov/entrez/...uids=16112652&query_hl=5&itool=pubmed_docsum" This had a section in the metohds and results which used specific cyp inhibitors.

The reference they used (#15) for specificity and concentration was also quite useful as a general guide to cyp involvment in metabolism and how to study it. http://www.ncbi.nlm.nih.gov/entrez/...uids=12814957&query_hl=7&itool=pubmed_docsum"

As far as cannabidiol-induced P450 inhibition - here are two articles.

http://www.ncbi.nlm.nih.gov/entrez/..._uids=9778318&query_hl=9&itool=pubmed_docsum".

http://www.ncbi.nlm.nih.gov/entrez/...uids=8466552&query_hl=11&itool=pubmed_docsum"

Happy hunting and let me know if you come across anything unfamiliar.

 

[gravenewworld]

You're awesome. thanks a bunch.

 

[DocToxyn]

You're awesome. thanks a bunch.

Well...I mean...ya' know... Thanks, and it's no problem.