Drug metabolism week 1 Flashcards
prodrugs
Prodrugs are pharmacologically inactive compounds designed to maximize the amount of the active species that reaches its site of action. Inactive prodrugs are converted rapidly to biologically active metabolites.
How are prodrugs often converted to active metabolites? Give an example of a clinical used prodrug.
Inactive prodrugs are converted rapidly to biologically active metabolites, often by the hydrolysis of an ester or amide linkage. Such is the case with a number of angiotensin-converting enzyme (ACE) inhibitors employed in the management of high blood pressure. Enalapril, for instance, is relatively inactive until converted by esterase activity to the diacid enalaprilat.
Explain the nomenclature of CYP450 enzymes.
Where in the body are CYP450s primarily located?
Where in the cell are CYP450 enzymes located?
What class of reactions do they perform?
What is their functional group?
- The enzyme systems involved in the biotransformation of drugs are localized primarily in the liver, although every tissue examined has some metabolism activity. Other organs with significant metabolic capacity include the GI tract, kidneys, and lungs. Following oral administration of a drug, a significant portion of the dose may be metabolically inactivated in either the intestinal epithelium or the liver before the drug reaches the systemic circulation. This so-called first-pass metabolism significantly limits the oral availability of highly metabolized drugs.
- Within a given cell, most drug-metabolizing activity is found in the smooth endoplasmic reticulum (see figure below) and the cytosol, although drug biotransformations also can occur in the mitochondria, nuclear envelope, and plasma membrane. Often, drugs biotransformed through a Phase I reaction are conjugated at this same site or in the cytosolic fraction of the same cell in a sequential fashion. Mammalian cytochrom P450s are membrane bound.
- redox (oxidation-reduction reactions)
- heme
What occurs in phase I reactions?
What is the purpose of phase I reactions? What are the results?
(Phase I) P450s catalyze four main types of chemical reactions: oxidation, reduction, hydrolysis and de-methylation. The reaction that is must important however is hydroxylation. Phase I is chemical modification in order to add a functional group that can be used to attach a conjugate. The conjugate makes the modified compound more water soluble so it can be excreted in the urine. Many P450s add a hydroxyl group in a Phase I step of drug metabolism. The hydroxyl then serves as the site for further modifications in Phase II drug metabolism.
Phase I reactions usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (–OH, –NH2, –SH). Often these metabolites are inactive, although in some instances activity is only modified or even enhanced.
Phase I reactions introduce or expose a functional group on the parent compound; for example, this occurs in hydrolysis reactions. Phase I reactions generally result in the loss of pharmacological activity, although there are examples of retention or enhancement of activity. In rare instances, metabolism is associated with altered pharmacological activity. Phase I reactions utilize Cyp450 (cytochrome) enzymes, located in the endoplasmic reticulum of the hepatocyte. (primary site of metabolism).
What occurs in phase II reactions? What kind of enzymes perform these reactions?
What are the results?
Give an example of a compound converted in a phase 2 reaction. Is this compound biologically active?
Phase II conjugation reactions, catalyzed by transferases, lead to the formation of a covalent (permanent) linkage between a functional group on the parent compound or Phase I metabolite and endogenously derived glucuronic acid, sulfate, glutathione, amino acids, or acetate. Such conjugation or synthetic reactions are the hallmarks of Phase II metabolism. These highly polar conjugates generally are inactive and are excreted rapidly in the urine and feces. An example of an active conjugate is the 6-glucuronide metabolite of morphine.
CYP450 enzymes are also used in endogenous biotransformation pathways. What do most of these enzymes use as substrates? What kind of things do they synthesize?
Biotransformation utilizing P450 pathways are integral to the biosynthesis of many mammalian compounds such as bile acids, hormones and eicosanoids. These enzymes tend to be in families with one or two members and they have only one substrate. Most of these enzymes use steroids or steroid precursors as their substrates.
Name the function of each of the CYP450 enzymes:
CYP5
CYP7A
CYP51
CYP5 is the thromboxane A2 synthase. Thromboxane A2 is a fatty acid in the arachidonic acid cascade. These enzymes are inhibited by aspirin and non-steroidal anti-inflammatory drugs (NSAIDS).
CYP7A is the first and rate limiting step of bile acid synthesis. This pathway is the only means the body has of eliminating cholesterol in liver.
CYP51 is key in making cholesterol from lanosterol, so P450s are active at both ends of cholesterol metabolism.
What are the two most imporant forms of the total human liver P450 content?
Explain their roles in drug metabolism.
CYP2D6 and CYP3A4
CYP2D6 is perhaps the best studied P450 with a drug metabolism polymorphism. This enzyme is responsible for more than 70 different drug oxidations. Since there may be no other way to clear these drugs from the system, poor metabolizers may be at severe risk for adverse drug reactions.
The CYP3A subfamily is one of the most important drug metabolizing families in humans. (>50% OF PRESCRIPTION DRUGS METABOLIZED BY THE LIVER) CYP3A4 is “the most abundantly expressed P450 in human liver.” CYP3A4 is known to metabolize more than 120 different drugs.
What is a polymorphism?
Give an example of a clinically significant polymorphism.
What is the signficance of polymorphisms as it pertains to NTI drugs?
A polymorphism is a difference in DNA sequence found in 1% or higher in a population. These differences in DNA sequence can lead to differences in drug metabolism, so they are important features of P450 genes in humans. CYP2C19 has a polymorphism that changes the enzyme’s ability to metabolize mephenytoin (an anticonvulsant).
Mutations in cytochrome P450 genes or deficiencies of the enzymes are responsible for several human diseases, as well as for alterations in metabolism. This is termed a POLYMORPHISM.
In Caucasians, the polymorphism for the poor metabolizer phenotype is only seen in 3% of the general population. However, it is seen in 20% of the Asian population. Because of this difference, it is important to be aware of a person’s race when drugs are given that are metabolized differently by different populations. Some drugs that have a narrow range of effective dose before they become toxic might be overdosed in a poor metabolizer.
What is an inducer? What are the effects?
Name drugs that induce CYP450 enzymes.
Inducers – ACCELERATE METABOLISM, LOWER THE EFFECT OF THE SUBSTRATE DRUG, and may rob the patient of the beneficial effect. Induction results in accelerated substrate metabolism and usually in a decrease in the pharmacologic action of the inducer and also of co-administered drugs. However, in the case of drugs metabolically transformed to reactive metabolite, enzyme induction may exacerbate metabolite-mediated toxicity.
Course notes: barbiturates, carbamazepine, glucocorticoids, rifampin, St. Johns Wort
Ethanol induces the CYP2E enzymes. This plays an important role in enhancing the toxicity of acetaminophen in alcoholics.
First Aid: Chronic Alcoholic Mona Steals Phen Phen and Never Refuses Greasy Carbs
Chronic alcholism
Modafinil
St. John’s wort
Phenytoin
Phenobarbital
Nevirapine
Rifampin
Griseofulvin
Carbamzepine
What is an inhibitor? What are the effects?
Name drugs that induce CYP450 enzymes.
Inhibitors – SLOW DOWN METABOLISM, INCREASE THE EFFECT OF THE SUBSTRATE DRUG AND MAY CAUSE TOXICITY OF THE SUBSTRATE.
Diltiazem, erythromycin, fluconazole, grapefruit juice and pulp (furanocoumarins), itraconazole, ketoconazole, ritonavir
There are common drugs given for special purposes that inhibit P450 enzymes. These include erythromycin (an antibiotic), ketoconazole, and itraconazole (both antifungals that inhibit the fungal CYP51 and unintentionally they also inhibit CYP3A4). If these drugs are given with other drugs that are normally metabolized by P450 enzymes, the half-life of these other drugs will be prolonged, and plasma levels will be increased, since they won’t be cleared as fast.
If the inhibited drugs affect heart rhythms or other critical systems, the result can be fatal. For example, inhibition of CYP3A4 in a patient taking warfarin can cause bleeding.
First Aid: A Cute Gentleman “Cipped” Iced Grapefruit juice Quickly And Kept Munching on Soft Cinnamon Rolls
Acute alcohol abuse
Gemfibrozil
Ciprofloxacin
Isoniazid
Grapefruit juice
Quinidine
Amiodarone
Ketoconazole
Macrolides
Sulfonamides
Cimetidine
Ritonavir
What chemicals in grapefruit juice inhibit CYP450s? Which CYP450 is inhibited? Where in the body? does the inhibition occur?
An important factor in drug dosage is interfering substances from food. Grapefruit (the fruit itself as well as the juice) contains a CYP3A4 inhibitor (furanocoumarins) that causes about a 12-fold increase in some drug concentrations. The inhibition is on the p-gp intestinal lining. The effect may last several days. It is advisable to discourage your patients from drinking grapefruit juice while on medication metabolized by CYP3A4. Pharmacists will automatically place caution labels on prescriptions for such medications. (Common in cholesterol lowering ‘statins’).
What are common endogenous detoxifying co-substrates?
GSH (glutathione), glucuronic acid, sulfate
Metabolism of drugs and other foreign chemicals may not always be an innocuous biochemical event leading to detoxification and elimination of the compound. Indeed, as previously noted, several compounds have been shown to be metabolically transformed to reactive intermediates that are toxic to various organs. Such toxic reactions may not be apparent at low levels of exposure to parent compounds when alternative detoxification mechanisms are not yet overwhelmed or compromised and when the availability of endogenous detoxifying co-substrates (GSH, glucuronic acid, sulfate) is sometimes limited. However, when these resources are exhausted, the toxic pathway may prevail, resulting in overt organ toxicity or carcinogenesis. The number of specific examples of such drug-induced toxicity is expanding rapidly.
Explain how tylenol may induce hepatotoxicity.
What is the role of alcohol in this pathway?
Acetaminophen is metabolized in the pathway depicted in the attached figure. It is metabolized via glucuronidation or sulfation. When metabolized via these routes, non-toxic metabolites are formed and excreted. If glutathione and/or sulfate stores are exhausted, the toxic intermediate NAPQI is formed. In the presence of alcohol, NAPQI is formed in even higher concentrations due to ethanol’s induction of CYP2E1, one of the enzymes repsonsible for formation of NAPQI.
Explain how age affects drug metabolism.
