Pharmacology
Summary
The CYP450 enzyme superfamily plays a crucial role in drug metabolism and the production of essential biomolecules, including hormones and cholesterol. Most notable of these enzymes is the CYP3A4 , responsible for metabolizing over 30% of drugs. Found primarily in the liver, specifically in the ER and mitochondria of hepatocytes, CYP450 enzymes also have a presence in other tissues. These enzymes not only polarize drugs for renal excretion but also convert some prodrugs into their active forms, as seen with codeine transforming into morphine. However, the activity of CYP450 enzymes varies among individuals due to genetic polymorphisms. This leads to variations in drug metabolism, with some individuals being ultra-rapid metabolizers, while others are poor metabolizers. For instance, CYP2D6 ultra-rapid metabolizers might experience toxicity from certain prodrugs, while poor metabolizers could face subtherapeutic effects.
Drug interactions with CYP450 enzymes can alter their activity, impacting the serum concentrations of some medications. Certain substances can induce or inhibit these enzymes. For example, common CYP450 inducers like St John’s wort, smoking, and RIFampin can increase drug metabolism, possibly reducing the serum concentrations of substrates. In such cases, doses of these substrates may need to be increased. On the other hand, inhibitors like macrolides, amiodirone, grapefruit juice, and certain antifungals such as ketoconazole can decrease drug metabolism, elevating serum concentrations. When co-administered with these inhibitors, substrate doses might require reduction to prevent potential adverse effects.
Lesson Outline
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FAQs
The CYP450 enzyme superfamily plays a significant role in producing essential molecules required for the body functions, including hormones and cholesterol. For instance, the aromatase enzyme (CYP19A1) converts androgens into estrogens. In drug metabolism, CYP450 enzymes work to metabolize or polarize drugs to make them ready for renal excretion. A characteristic example is CYP3A4, which metabolizes over 30% of drugs, making it the highest among all CYP450 enzymes. CYP450 enzymes also aid in converting prodrugs into their active forms. Genetic variations can affect the activity of CYP450 enzymes between individuals, leading to differences in drug metabolism rates.
CYP450 enzymes are primarily expressed in the liver, within the endoplasmic reticulum and mitochondria of hepatocytes. They are also present in other parts of the body. Their concentration in the liver plays a critical role in the metabolism and excretion of drugs.
Because of genetic variation, some individuals metabolize certain drugs more quickly than others. Those who metabolize drugs rapidly are known as "ultra-rapid metabolizers." They may require higher drug doses for efficacy, or they may experience toxicity from certain prodrugs, such as codeine. On the other hand, "poor metabolizers" metabolize drugs more slowly, which could lead to subtherapeutic levels of certain prodrugs, resulting in poor effectiveness, e.g., inadequate pain management when using codeine.
CYP450 inducers increase the metabolic activity of CYP450 enzymes, which can result in decreased serum concentrations of certain drugs. Notable inducers include St John’s wort, smoking, and the antibiotic, rifampin. On the other hand, CYP450 inhibitors reduce the activity of CYP450 enzymes, which can increase drug serum concentrations. Common inhibitors include macrolides, amiodarone, non-dihydropyridine calcium channel blockers, grapefruit juice, and azole antifungals. These factors must be considered, as it may be necessary to adjust drug doses when used with CYP450 inducers or inhibitors.
When a patient is administered drugs alongside CYP450 inducers, it may require an increase in substrate doses. This is due to the increased metabolic activity that significantly decreases drug serum concentrations. Conversely, when drugs are taken with CYP450 inhibitors, a decrease in the substrate doses might be necessary. This is because the inhibitors slow down CYP450 enzyme activity, thereby increasing drug serum concentrations. Ultimately, considering these factors can help to ensure effective treatment while minimizing the risk of drug toxicity.
