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
