1.2 Drug Metabolism Flashcards
What are examples of lipophilic tissues
breast tissues, adipose tissues, testicular tissues.
Where are sites for drug metabolism?
liver (major organ), gut, kidneys, skin, brain
What are Phase I reactions?
Oxidation, Reduction, Hydrolysis
functional group
[CYP family- specificity]
Because there are many different genes that encode multiple enzymes, there are many different P450 isoforms. These enzymes have the capacity to modify a large number of structurally diverse substrates. In addition, an individual drug may be a substrate for more than one isozyme. Four isozymes are responsible for the vast majority of P450-catalyzed reactions. They are CYP3A4/5, CYP2D6, CYP2C8/9, and CYP1A2 (Figure 1.17). Considerable amounts of _______ are found in intestinal mucosa, accounting for first-pass metabolism of drugs such as chlorpromazine and clonazepam.
CYP34A4
[CYP family- specificity]
Many enzymes can use a single substrate due to ________ but low efficiency of catalysis; prominent substrates include warfarin, anticonvulsants, theophylline and the oral contraceptive pill
broad specificity
[CYP family- genetic variability]
P450 enzymes exhibit considerable genetic variability among individuals and racial groups. Variations in P450 activity may alter drug efficacy and the risk of adverse events. ______ in particular, has been shown to exhibit genetic polymorphism. CYP2D6 mutations result in very low capacities to metabolize substrates. Some individuals, for example, obtain no benefit from the opioid analgesic ______, because they lack the CYP2D6 enzyme that activates the drug
CYP2D6; codeine
CYP family- genetic variability]
_______ carries a warning that patients who are poor CYP2C19 metabolizers have a higher incidence of cardiovascular events (for example, stroke or myocardial infarction) when taking this drug. Clopidogrel is a prodrug, and CYP2C19 activity is required to convert it to the active metabolite
Clopidogrel
What are inducers?
Certain drugs (for example, phenobarbital, rifampin, and carbamazepine) are capable of increasing the synthesis of one or more CYP isozymes. This results in increased biotransformation of drugs and can lead to significant decreases in plasma concentrations of drugs metabolized by these CYP isozymes, with concurrent loss of pharmacologic effect
[CYP family- inducers]
____, an antituberculosis drug , significantly decreases the plasma concentrations of human immunodeficiency virus (HIV) protease inhibitors, thereby diminishing their ability to suppress HIV replication
Rimfampin
[CYP- family inducers]
St. John’s wort is a widely used herbal product and is a potent ______ inducer. Many drug interactions have been reported with concomitant use of St. John’s wort
CYP3A4
[CYP family- inhibitors]
Inhibition of CYP isozyme activity is an important source of drug interactions that lead to serious adverse events. The most common form of inhibition is through competition for the same isozyme. Some drugs, however, are capable of inhibiting reactions for which they are not substrates (for example, ___________), leading to drug interactions.
ketoconazole
[CYP family- inhibitors]
Numerous drugs have been shown to inhibit one or more of the CYP-dependent biotransformation pathways of warfarin. For example, _________ is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism. If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater anticoagulant effect and increased risk of bleeding
omeprazole
[CYP family- inhibitors]
What are the more important inhibitors?
erythromycin, ketoconazole, and ritonavir
[CYP family- inhibitors]
Natural substances may also inhibit drug metabolism. For instance, grapefruit juice inhibits _______ and leads to higher levels and/or greater potential for toxic effects with drugs, such as nifedipine, clarithromycin, and simvastatin, that are metabolized by this system.
CYP3A4
[Phase 1 Metabolism- biochemistry]
1) In the presence of __________________, cytochrome P450 oxidises the drug into a hydroxylated derivative generating NADP+ and H2O in the process
2) In the normal state, P450 exists as a heme protein with an Fe3+ in the centre of the molecule
3) Upon interaction with the enzyme, the drug binds to the oxidised iron at the active site by forming a ligand with the oxidised ion
4) An electron is donated from NADPH into the P450 molecule, reducing the iron from Fe3+ to Fe2+
O2 becomes bound to the complex at the catalytic site
5) The molecule is rearranged and the electron is donated to O2, restoring Fe2+ to Fe3+
6) Another electron is again donated to Fe3+ by NADPH to form Fe2+, followed by another rearrangement where the electron is donated to O2, restoring Fe3+ and now oxygen has 2 additional electrons and now is very reactive.
7) Metabolism of the drug forms the hydroxylated derivative where one atom of O2 goes into the drug
and the other _______
9) The final step involves the release of the oxidised drug and recycling of the P450 enzyme
NADPH (provides reducing power), O2 and H+; combines with H2 to form H2O
[Aromatic Oxidative]
___________ is a prodrug for paracetamol but is not administered directly as it is toxic
Acetanilide
What are examples of oxidative reactions?
Aliphatic, Aromatic, N-demethylation, O-demethylation, N-oxidation, Alcohol Oxidation
[N-oxidation]
- Trimethylamine is a substrate for _______ (FMO) which performs the same oxidation reaction as cytochrome P450
- Results in donation of the lone pair of electrons on the N atom to the O atom, forming a ______
- In individuals with fish odour syndrome, defective FMO enzyme results in inability to convert trimethylamine to trimethylamine oxide; as trimethylamine is lipophilic, these individuals localise trimethylamine, which smells strongly of fish, in their fatty tissues
- Healthy individuals convert trimethylamine to ____, which is odourless and highly polar, and therefore readily excreted in urine
flavin-containing monooxygenase; dative bond; N-oxide
[Alcohol Oxidation]
- Ethanol is converted to _______ by alcohol dehydrogenase (reversible reaction)
- Acetaldehyde is converted to acetic acid.
acetaldehyde
[Reduction]
Cleave of the _____ bond is catalyzed by a reductase enzyme
N=N
[Hydrolysis]
________ are hydrolyzed by esterases and amidases respectively
Esters and amides
Phase II: A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are often therapeutically inactive. A notable exception is __________, which is more potent than morphine. _______ is the most common and the most important conjugation reaction.
morphine-6-glucuronide; Glucuronidation
[Note: Drugs already possessing an ___________ group may enter phase II directly and become conjugated without prior phase I metabolism.] The highly polar drug conjugates are then excreted by the kidney or in bile
–OH, –NH2, or –COOH
[Phase 2 metabolism]
- Consist conjugation reactions involving an endogenous substrate and metabolites from Phase I which are rarely sufficiently polar to be excreted by the kidneys
- All reactions involve a ________(high energy intermediate acting as a cofactor which is involved in the transfer of endogenous usually acidic group to the xenobiotic to polar)
conjugating agent
What do Phase II reactions include?
Glucuronidation, Acetylation, Amino Acid conjugation, Methylation, Sulphation, Gluthathione conjugation
Glucuronidation
- enzyme
- conjugating agent
- target functional group
- Glucuronyl transferase
- UDP - Glucuronic acid
- OH, COOH, NH2, SH
Acetylation
- enzyme
- conjugating agent
- target functional group
- Acetyl transferase
- Acetyl CoA
- OH, NH2
Amino Acid conjugaton
- enzyme
- conjugating agent
- target functional group
- Acyl transferase
- Glycine, Glutamine,Taurine
- COOH
Methylation
- enzyme
- conjugating agent
- target functional group
- Methyl transferase
- 5-Adenosylmethionine
- OH, NH2
Sulphation
- enzyme
- conjugating agent
- target functional group
- Sulfotransferase
- 3’ Phosphoadenosine-5’Phosphosulfate
- OH, NH2
Gluthathione Conjugation
- enzyme
- conjugating agent
- target functional group
- Gutatjione- S- transferase
- Glutathione
- Electrophiles
- Drug metabolism reduces biological half-life of chemicals, resulting in decreased duration of exposure
- Hence, accumulation of compound in the body is avoided
- Chemicals (e.g. ______) that undergo low metabolism have a long half-life in the body
- Potency/duration of biological activity of chemicals can be altered by drug metabolism
- Pharmacology/toxicology of drugs can also be governed by metabolism e.g. activating prodrugs or inactive drug
dioxins
