Concept of p450 Metabolism

[aspiringmd1015]

Confused about the p450 metabolism, is it used to make drugs excretable purely in the bile/gut? or are they also broken down to water soluble compounds that can be urinated out?

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[animando]

Both. But they are not really "broken down"

 

[aspiringmd1015]

yeah sorry meant metabolized. so what determines what is metabolized in the liver and what isnt? my pre-understanding was that its going to the liver to be metabolized so it could be consequently excreted in the bile

 

[animando]

I wasn't picking on you about terminology ^^ Just wanted to point out that the liver adds molecules on drugs rather than removing them. I don't think you can predict the excretion pathway for sure with general rules.

For example (just found this on the web) PK of phenobarbital (the first drug I thought in this case):

Barbiturates are metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine and, less commonly, in the feces. Approximately 25% to 50% of a dose of Phenobarbital is eliminated unchanged in the urine...

As my biochemistry teacher said: the liver has no idea of what it is doing. It just picks stuff, does some phase 1&2 reactions and sees what happens.

 

[Distant]

CYP3A4 ........
High Yeild

 

[aspiringmd1015]

I wasn't picking on you about terminology ^^ Just wanted to point out that the liver adds molecules on drugs rather than removing them. I don't think you can predict the excretion pathway for sure with general rules.

For example (just found this on the web) PK of phenobarbital (the first drug I thought in this case):


As my biochemistry teacher said: the liver has no idea of what it is doing. It just picks stuff, does some phase 1&2 reactions and sees what happens.

what about strictly lipid soluble drugs? they cant be excreted in the urine, so they must be metabolized by the liver and thus excreted in the bile? and if tahts so is the only way to metabolize them in the liver by the cp450 enzymes?(ie tolcapone which is lipid soluble, and thus also hepatotoxic)

 

[animando]

Tolcapone is metabolized by the liver but after is excreted in the bile (40%) and the urine (60%) (Wiki says so). Once made water soluble, a drug can return to the blood and be excreted by the kidneys. Metabolism and excretion are two different things and don't need to take place in the same organ.

 

[aspiringmd1015]

so is there a particular reason/association of why certain drugs are excreted in bile?

 

[Slade009]

The urine and bile are the 2 main ways of drugs excretion, other ways are tears, saliva, sweat and lungs (gases, vapors and alcohol). Drugs that are excreted in the urine or bile are mostly water-soluble (polar). Usually when a drug is initially absorbed it goes through the liver (first pass) after conjugation it is excreted through bile (I'm only talking about bile excretion here). Metabolites of certain drugs are excreted into the intestines and then commonly undergo Hepatic Cycling (hyrdoconjugation) which then reabsorbs it back into circulation for a second time which tends to decrease the net excretion of this route. Pertaining to your question now, what you are asking is basically:

What Factors determine the process of elimination?

Answer:- Great question and very clinically relevant also. From my knowledge the factors are chemical structure, polarity and molecular size that determine it all.

IF a drug is fat-soluble, a small particle, basic in nature, easy to absorb, chances are it's getting metabolized and excreted by the liver and is possibly hepatotoxic at high levels.
IF a drug is water-soluble, a large particle, acidic in nature, hard to absorb, chances are it's being renally excreted and at high doses possibly nephrotoxic.
The clinical correlation is basically if a drug has a long half life it will most likely be fat-soluble and so on and so forth but I won't be explaining that since this is for Step 1. Don't get bogged down into the minute details.
Hope this helped clear things up. Msg me if you still want the clinical details also.