Factors Affecting Drug Metabolism – Biotransformation | Pharmacokinetics (PK)

by Pravin Shukle, MD

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    00:01 What are the factors that affect drug metabolism. Well you have genetic differences of cytochrome P450. You can have competitive inhibition of Cytochrome P450. You can have direct inhibition. You can have induction. You can inhibit P-Glycoprotein and you can alter blood flow. So all of these things are going to affect the way that we metabolize our drugs. Now racial factors affect Cytochrome P450 activation. So for example let's talk about -2D6. So -2D6 is one of the isoenzymes. It has four different phenotypes. They are the poor metabolizers. These are men and women who have two inactive allelles. Then you have the intermediate metabolizers. These are heterozygotes. They inherited one active allelle from their mother and perhaps an inactive allelle from their father. So they have one active one inactive allelles. So they are heterozygotes. They have a moderate amount of activity. You have extensive metabolizers.

    01:08 So they inherited from each parent an active allele. So these are very extensive metabolizers. They will bring down the drug level and convert it to the daughter drug very quickly. There is a fourth category. These are the ultrarapid metabolizers.

    01:23 Some patients will have multiple copies of their genes that will code for very active Cytochrome systems. Here is an example of what we are talking about. So this a drug called nortriptyline it's an antidepressant. Let's take a look at a person who has 0 functional 2D6 genes. There is the binding curve, okay. Sorry it's a concentration curve. Now let's look at a concentration curve when a person has 1 functional gene or 2 functional genes or 3 functional genes or in fact 13 functional genes. So the more functional genes for that 2D6 you have the lower your drug level and the less active that drug is going to be in that body and the more drug you need to prescribe for that person. Or perhaps just use a different drug. Cytochrome is like a bridge and imagine you are driving in a car. As long as the bridge is empty, you can drive across it very quick. Two drugs may compete for that same pathway. So if you have too many cars trying to cross the bridge it's going to take a long time getting across that bridge. One drug may actually inhibit the metabolism of another.

    02:38 So if you have a person who is driving really slow in a car then eventhough there is not too many cars around that one person can slow down an entire chain of cars. So that's what an inhibitor does on the cytochrome system. Now one drug may induce the metabolism of another. So if you ever seen ambulance, as you always know that there is at least a one idiot following the ambulance at a really high speed. That's like an induction enzyme. You've got 1 drug that makes the metabolism of another drug very quick. The opposite is true when the active drug is the metabolite. So I want you to imagine now that instead of having the active drug as the parent drug you've got the active drug as the daughter drug.

    03:23 So good example of that is codeine. Codeine is converted to an analogue of morphine via the cytochrome system 2D6.

    03:31 So people who are fast metabolizers will have a much more potent shorter term response. So genetic factors that we talked about earlier with our plants are going to affect how we metabolize drugs. And a really good example is that let's take a look at patients who immigrate to the United States from ethnic Northern European countries. These patients 10% of your ethnic European/Nordic American patients will have little therapeutic effect from codeine. So you have to use higher doses of codeine or perhaps which to actual morphine to treat them. On the other hand when you take a look at patients from the African subcontinent, from the African continent, 30% of your ethnic African American patients will be hypermetabolizers.

    04:22 So they will be exposed to excessively high levels of morphine when they take a small dose of cedeine. Being aware of racial differences is very important. But also being aware of inhibitors of cytochrome system is important too.

    04:36 So I'm going to go through each of this drugs in detail. Amiodarone inhibits cytochrome. Fluconazole which is an antifungal agent inhibits cytochrome. Cimetidine; Ritonavir, which is HIV drug and grapefruit juice are all inhibitors of cytochrome system. You should memorise this list. You need to know this list cold, okay. So although I hate telling people to memorise lists without thinking about them, in this particular case you need to memorise this without thinking about it because you need to be able to rattle off these drugs and of course grapefruit juice as inhibitors of cytochrome.

    05:18 Cytochrome P450 also has suicide inhibitors. So what's a suicide inhibitor? It means that it's permanently inhibiting things.

    05:26 So spirinolactone which is a antihypertensive agent is a suicide inhibitor. Ethinyl estradiol which is a hormone agent and is also used as a contraceptive agent is one. Allopurinol is another. Propylthiouracil which is an anti-thyroid medication and secobarbital which is an antiepileptic. Now I just want to mention something special about secobarbital.

    05:52 This antiepileptic drug is always the one that trips up medical students and it certainly gotten me when I wrote my exam.

    06:00 So I got this wrong. And we're going to spend a little bit of extra time on secobarbital and the other antiepileptics with respect to the cytochrome system and I'll show you why later. Once again I want you to memorise this list of drugs.

    06:12 You need to know them for your exam and honestly you need to know them for a clinical practice as well. Now there are also inducers of cytochrome system and I've put them in green so you can remember that they make things go faster. The prototypical inducer is Rifampin. It is also the most powerful inducer. It's a drug that we almost never use in real world clinical practice but whenever you look at a drug, the first thing that will say on the drug interaction list is always Rifampin. And it's used as a testing agent. Carbamazepine or Tegretol is used as an anti-seizure medication. Phenobarbital is an anti-seizure medication. Phenytoin or Dilantin is an anti-seizure medication. Ethanol is of course alcohol. And St.John's Wort is a herbal product that has been particularly problematic for a lot of our patients. You should memorise this list.

    07:09 Now I'd like to talk to you quickly about St.John's Wort. St. John's Wort is a herbal product that is used in the treatment of depression. It's somewhat effective. In fact it's efectiveness is greatly exagerrated by the press. But one of the most important things that we need to know about St.John's Wort is it's effect on drugs. Now people can die if they take St.John's Wort in combination with their medication. Here is a paper that was released some time ago where heart transplant rejection occured due to St.John's Wort. So this patients who received heart transplants took St.John's Wort and it interacted with their antirejection medications causing heart transplant rejection. In other words, death. So it's a terrible type of drug reaction that was caused by something that we were'nt really aware of in the medical community. So it's always important when you're talking to your patients to get them to give you a list of the herbal products they take and preferably stop them all. Now let's go back to that P-Glycoprotein that we were talking about. The P-Glycoprotein or MDR inhibitors. So we have a whole list of them. P-Glycoprotein, I'm going to repeat this, is also called MDR-1. It is a transport protein and it moves drug from outside the cell into cells or into intestinal lumen. Inhibiting MDR at the gene level causes toxic levels of a drug. So here are inhibitors of P-Glycoprotein, verapamil and grapefruit. And substrates of P-Glycoprotein are cyclosporine and digoxin. So cyclosporin can be affected quite significantly by grapefruit or by verapamil.

    08:54 You need to memorise this list of P-Glycoprotein or MDR-1 inhibitors and substrates. Okay, so here is a list of everything.

    09:06 I want to just point out something about secobarbital and the anti-seizure medications. And when you take particular attention the inducers are generally antiseizure medications except for secobarbital which is a suicide inhibitor, okay. So all seizure medication, all antiseizure medications are inducers of cytochrome. You can see carbamazepine, phenobarbital, phenytoin and ethanol.

    09:32 Ethanol is'nt really an antiseizure med but you know what I mean. Secobarbital is a suicide inhibitor. It is different.

    09:39 It's very important to remember that and it's often things that trip up medical students. Okay, let's do a question.

    09:48 This is a drug interaction in the coronary care unit. A 55-year old man was diagnosed with atrial fibrillation. His cardiologist prescribed verapamil. He was later found to have atrial fibrillation rhythm with a ventricular rate of 136 bpm.

    10:04 His nurse practitioner prescribed digoxin to help with his rate control. Which of the following is false? The verapamil and digoxin both cause a reduction in heart rate; B. The verapamil is metabolized through the same Cytochrome P450 system and may interact based on a common final pathway. Verapamil is a MDR-1 inhibitor and may result in digoxin toxicity. Or D. Digoxin is cleared by the P-Glycoprotein transport molecule. Which is false? Well let's look at our list and let's look at our answer. So the answer is B, this is wrong. The verapamil is metabolized through the same Cytochrome P450 system and may interact based on a common final pathway. The truth is, is verapamil is an MDR-1 inhibitor. It may result in digoxin toxicity. The mechanism of verapamil is to reduce blood pressure and to reduce heart rate and also digoxin will reduce heart rate. So A is correct, C is correct and D is correct because digoxin is cleared by P-Glycoprotein.

    11:17 Remember that P-Glycoprotein and MDR-1 we are talking about the same thing. Let's look at another question.

    11:26 Realizing Rifampin relevance. I love illiterations and you will see that commonly with my lectures.

    11:33 A new drug is tested at Gargantua Pharmaceuticals. The scientist administers rifampin along with the new drug to look for the risk of drug interactions. The following is true, so pick one answer that's true. So the answer, it is induced by rifampin.

    11:59 So take a look at the question. You've got a lot of inhibited there. 2D6, 3A4, 3A5 is inhibited by rifampin. And then you have one answer that's induction and then finally the fifth answer is P-GP is induced by rifampin. Well that's not true and it's certainly not an inhibitor. Rifampin is an inducer of cytochrome and it actually induces most of the isoenzymes.

    12:24 So the correct answer is D. Let's do a question of cytochrome isoenzymes. Which of the following cytochrome isoenzymes is the most active in metabolizing drugs. Is it 1A2; Is it 2C9: 2C19; 2D6 or 3A4/5. The answer is always 3A4/5 and when you're looking at an exam, 3A4/5 is going to be your answer. And when you're out in clinical practice, you are going to need to know if your drug is metabolized through 3A4/5 because almost certainly that patient's other drug will be too. Okay, let's look at a question for inducers of cytochrome P450. Which of the following drugs is the most powerful inducer of Cytochrome P450? Is it Abciximab? Is it Verapamil? Is it Phenobarbital? Is it Acetaminophen? or is it Rifampin? The answer is Rifampin. So remember Rifampin is your prototypical inducer. It is also the most widespread inducer and the most powerful inducer. Let's do a question on a common problem. A 45-year-old male with epilepsy is placed on the cholesterol lowering agent simvastatin. He returns with severe myalgias, and elevated liver enzymes. You suspect that he developed statin toxicity. Which of these medications could be causing this? Could it be Rifampin. Could it be Carbamazepine.

    13:56 Could be an increase in alcohol intake. Could it be Phenytoin or could it be secobarbital. The answer is secobarbital.

    14:04 So remember that secobarbital is different from the other antiseizure medications. Look at that. A suicide inhibitor secobarbital. The other antiseizure medications are inducers. Okay let's do a question on suicide inhibitors of cytochrome P450.

    14:23 Which of the following is not a suicide inhibitor? Is it secobarbital; phenobarbitol; ethinly estradiol; spirinolactone or propylthiouracil. Good, you answered B, phenobarbital. It's really important to remember that you have a choice between secobarbital and phenobarbital, and secobarbital is a suicide inhibitor. It is one of those rare anti-seizure medications that is an inhibitor. Most other antiseizure medications are inducers. The suicide inhibitors are allopurinol, ethinyl estradiol, propylthiouracil and secobarbital. And I would definitely reccomend that you memorise this list of drugs.

    15:13 Well that's it, thank you very much.

    About the Lecture

    The lecture Factors Affecting Drug Metabolism – Biotransformation | Pharmacokinetics (PK) by Pravin Shukle, MD is from the course Pharmacokinetics and Pharmacodynamics. It contains the following chapters:

    • Factors Affecting Drug Metabolism
    • Interactions of CYP450
    • Inhibitors & Inducers of CYP 450
    • P-Glycoprotein Inhibitors
    • Case Study: Drug Interaction in the CCU
    • Questions and Case Study

    Included Quiz Questions

    1. Experience lower drug levels than a heterozygote.
    2. Experience prolonged activity when compared to a person with no active alleles.
    3. Experience higher drug concentrations and prolonged drug activity than a heterozygote.
    4. Experience higher drug concentrations and shortened activity than a heterozygote.
    1. Spironolactone
    2. Amiodarone
    3. Grapefruit juice
    4. Cimetidine
    5. Fluconazole
    1. Increase dose of drug (A) since St. John’s Wort is a CYP450 inducer.
    2. Increase the dose of drug (A) since St. John’s Wort is a CYP450 suicide inhibitor.
    3. Decrease the dose of drug (A) since St. John’s Wort is a CYP450 suicide inhibitor.
    5. Decrease the dose of drug (A) since St. John’s Wort is a CYP450 inhibitor.
    1. The drug is administered with a cytochrome inducer.
    2. The drug is given to a patient with few active metabolic alleles.
    3. The drug is given to a patient who cannot metabolize the drug.
    4. The drug is given to a patient who had ingested a suicide inhibitor of cytochrome.

    Author of lecture Factors Affecting Drug Metabolism – Biotransformation | Pharmacokinetics (PK)

     Pravin Shukle, MD

    Pravin Shukle, MD

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    Very helpful primer on CYP and PGP issues.
    By Matt M. on 19. April 2020 for Factors Affecting Drug Metabolism – Biotransformation | Pharmacokinetics (PK)

    This is a great overview of CYP and PGP issues. Drug biotransformation is a very complex topic and this is an excellent primer on some key issues. I hope to see more like this.