please help a second year dental student with these questions

[fightingspirit]

I have asked these questions to medical students and to the professor here at my school. None had the answer. So I figured that a senior pharm student may be able to handle these questions.

this is about the liver’s role in a drug’s half-life.
With respect to most drugs that are metabolized by the liver, it seems that the liver metabolizes them into an INACTIVE metabolite. Assuming drug A follows these kinetics, then it is clear why a person who has a hyperactive liver needs a larger dose. However, some drugs get metabolized into an ACTIVE form. Assuming drug B follows this pattern, then what would be the adjustment, if any, in a person with a hyperactive liver and who needs to take this drug for a long while? Would the steady state plasma level decrease, increase, or remain the same, if you change the dose in order to adjust for the hyperactive liver for drug B?
If drug C is an anticancer drug that gets metabolized by the liver into an ACTIVE form, then would your answers for drug B adjustment apply? I ask this question because anticancer drugs are special in the sense that they are administered as large doses over extended intervals.

thank you

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[Requiem]

Assuming drug B follows this pattern, then what would be the adjustment, if any, in a person with a hyperactive liver and who needs to take this drug for a long while? Would the steady state plasma level decrease, increase, or remain the same, if you change the dose in order to adjust for the hyperactive liver for drug B?

I'm on my way to the gym so I don't have a lot of time but I'll give you a brief explanation. The drugs you're referring to are called pro-drugs; and there are certain conditions in diff. pt. populations [i.e fast/slow acetylators] whereby drug metabolism is influenced by genetic differences.

Dosing adjustments are usually performed in patients with rapid inactivation, I've never seen nor heard of [I'm a third year] of dosing adjustment based on rapid metabolic reactions from prodrug -> active drug. One major problem, which does require does adjustment is with drugs that have toxic metabolites, and toxicity _is_ amplified by rapid metabolism [i.e CYP induction]. Efficacy also decreases with CYP induction, and doses often have to be elevated.. you're revving up your liver enzymes. Think PI HIV meds.

One difference here with inactivation vs activation is you're getting a more rapid production of a toxic metabolite, resulting in higher serum levels of it. This requires adjustment. Since pro-drugs will only have a certain % of bioavailability, regardless of whether it's instantaneously converted or over time your serum concentration can't spike that much higher imo. I'd wager steady state levels would be very similar. It would be a more rapid climb in concentration, which is actually desirable a la IV vs PO.

If somehow the bioavailability is increased, you'd have to monitor levels to make sure they don't reach toxic levels. Here steady state would increase. That's my stab at it. Cheers. If you have more questions just reply, I'll be around later.

 

[NewRx]

I'm on my way to the gym so I don't have a lot of time but I'll give you a brief explanation. The drugs you're referring to are called pro-drugs; and there are certain conditions in diff. pt. populations [i.e fast/slow acetylators] whereby drug metabolism is influenced by genetic differences.

Dosing adjustments are usually performed in patients with rapid inactivation, I've never seen nor heard of [I'm a third year] of dosing adjustment based on rapid metabolic reactions from prodrug -> active drug. One major problem, which does require does adjustment is with drugs that have toxic metabolites, and toxicity _is_ amplified by rapid metabolism [i.e CYP induction]. Efficacy also decreases with CYP induction, and doses often have to be elevated.. you're revving up your liver enzymes. Think PI HIV meds.

One difference here with inactivation vs activation is you're getting a more rapid production of a toxic metabolite, resulting in higher serum levels of it. This requires adjustment. Since pro-drugs will only have a certain % of bioavailability, regardless of whether it's instantaneously converted or over time your serum concentration can't spike that much higher imo. I'd wager steady state levels would be very similar. It would be a more rapid climb in concentration, which is actually desirable a la IV vs PO.

If somehow the bioavailability is increased, you'd have to monitor levels to make sure they don't reach toxic levels. Here steady state would increase. That's my stab at it. Cheers. If you have more questions just reply, I'll be around later.

Whoa! That was super cool! Anyone still need to know what pharmacists do! I admit, I had no idea what was being said, but I'm sure that'll change when I'm a P3!

 

[Aznfarmerboi]

. Assuming drug A follows these kinetics, then it is clear why a person who has a hyperactive liver needs a larger dose. However, some drugs get metabolized into an ACTIVE form. Assuming drug B follows this pattern, then what would be the adjustment, if any, in a person with a hyperactive liver and who needs to take this drug for a long while?

If drug A follows these kinetics, you would want to decrease the patients dose or frequency as this would lead to an overaccumulation concentration of drug causing toxicities. Remember, too much of anything is a bad thing.

Would the steady state plasma level decrease, increase, or remain the same, if you change the dose in order to adjust for the hyperactive liver for drug B?

The rate to steady state will change accordingly to the dose (it might increase or decrease). However the time to steady state will still stay the same.

 

[Tuck]

. Assuming drug A follows these kinetics, then it is clear why a person who has a hyperactive liver needs a larger dose. However, some drugs get metabolized into an ACTIVE form. Assuming drug B follows this pattern, then what would be the adjustment, if any, in a person with a hyperactive liver and who needs to take this drug for a long while?

If drug A follows these kinetics, you would want to decrease the patients dose or frequency as this would lead to an overaccumulation concentration of drug causing toxicities. Remember, too much of anything is a bad thing.

Would the steady state plasma level decrease, increase, or remain the same, if you change the dose in order to adjust for the hyperactive liver for drug B?

The rate to steady state will change accordingly to the dose (it might increase or decrease). However the time to steady state will still stay the same.

Maybe I am unclear, but if I read it right it seems that in case A the drug is undergoing increased metabolism to the inactive form reducing the activated drug that is circulating. In any case, the answer will depend on the theraputic window of the drug and the half lives of the parent drugs and the metabolites. If the metabolism of the drug to an inactive form prevents it from maintaining the MIC then increasing the dose will likely be necessary. However, there are some drugs that have metabolites that half very long half lives and if they happen to be toxic and are not being cleared adequately you can run into a situation where you have to choose if the benefits of keeping the person on the drug outweigh the negatives from the toxcities.

 

[fightingspirit]

I'm on my way to the gym so I don't have a lot of time but I'll give you a brief explanation. The drugs you're referring to are called pro-drugs; and there are certain conditions in diff. pt. populations [i.e fast/slow acetylators] whereby drug metabolism is influenced by genetic differences.

Dosing adjustments are usually performed in patients with rapid inactivation, I've never seen nor heard of [I'm a third year] of dosing adjustment based on rapid metabolic reactions from prodrug -> active drug. One major problem, which does require does adjustment is with drugs that have toxic metabolites, and toxicity _is_ amplified by rapid metabolism [i.e CYP induction]. Efficacy also decreases with CYP induction, and doses often have to be elevated.. you're revving up your liver enzymes. Think PI HIV meds.

One difference here with inactivation vs activation is you're getting a more rapid production of a toxic metabolite, resulting in higher serum levels of it. This requires adjustment. Since pro-drugs will only have a certain % of bioavailability, regardless of whether it's instantaneously converted or over time your serum concentration can't spike that much higher imo. I'd wager steady state levels would be very similar. It would be a more rapid climb in concentration, which is actually desirable a la IV vs PO.

If somehow the bioavailability is increased, you'd have to monitor levels to make sure they don't reach toxic levels. Here steady state would increase. That's my stab at it. Cheers. If you have more questions just reply, I'll be around later.

thank you very much.

i understand how a person who is a fast activator of a prodrug gets a faster rise of plasma concentration of the active drug, and that this may be a desirable effect if the concentration reached is the therapuetic one. but one can consider the blood to be a reservoir of the prodrug. this means that this person will also have less prodrug in the circulation for subsequent cycles due to the initial activation of a large chunk of the prodrug. a normal person will activate the prodrug at a lower rate, resulting in higher prodrug concentration and thus longer half life???

 

[Aznfarmerboi]

i understand how a person who is a fast activator of a prodrug gets a faster rise of plasma concentration of the active drug, and that this may be a desirable effect if the concentration reached is the therapuetic one. but one can consider the blood to be a reservoir of the prodrug. this means that this person will also have less prodrug in the circulation for subsequent cycles due to the initial activation of a large chunk of the prodrug. a normal person will activate the prodrug at a lower rate, resulting in higher prodrug concentration and thus longer half life???

Your thinking is wrong in the sense that the rate a drug is metabolized and excreted is a constant. If you have a hyperactive liver, it will metabolized that drug constantly (think of it as a factory). Thus, the person does not have a lower rate, resulting in higher prodrug concentration, and thus longer half life.
In addition to that, you are oversimplyfying things. There are many factors such as if the the drug has a low molecular weight or high molecular weight, if the liver is being perfused at a fast or low rate, how the drug distributes, etc.

 

[Requiem]

thank you very much.

i understand how a person who is a fast activator of a prodrug gets a faster rise of plasma concentration of the active drug, and that this may be a desirable effect if the concentration reached is the therapuetic one. but one can consider the blood to be a reservoir of the prodrug. this means that this person will also have less prodrug in the circulation for subsequent cycles due to the initial activation of a large chunk of the prodrug. a normal person will activate the prodrug at a lower rate, resulting in higher prodrug concentration and thus longer half life???

No problem.

I understand your reasoning, but I think you misunderstand how a drug gets into the bloodstream.

A drug gets absorbed in your stomach or small intestine, whereby _hepatic_ portal veins bring it to the liver where it is metabolized _before_ it reaches systemic circulation. The drug doesn't circulate throughout the bloodstream as a prodrug, it's converted in the liver to it's active form [sometimes stomach or intestinal enzymes do it as well] _before_ it reaches systemic circulation. So in your hypothetical case of the rapid metabolizer [from prodrug to drug] the half life would be shortened by a negligble amount.