Sandbox CYPMetabolism: Difference between revisions
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== Irreversible inhibition of CYP450s== | == Irreversible inhibition of CYP450s== | ||
When we examined CYP1A2 above, the flavone inhibited the enzyme simply by virtue of having such complementary features to the binding site. It binds so tightly that it physically prevents other drugs from binding to it. Another way that a drug can inhibit CYP450 enzymes is by formation of a covalent bond that deactivates the active site. This happens with a well-known inhibitor of CYP3A4, <scene name='60/609993/Ritonavir/1'>ritonavir</scene>. Ritonavir is a HIV protease inhibitor routinely prescribed in combination with other antivirals. Its efficacy as part of a drug "cocktail" stems from the fact that it is a potent "irreversible inhibitor" of CYP3A4. Irreversible inhibition differs from most cases of competitive inhibition in that the enzyme is permanently deactivated, and must be re-synthesized by the cell. | When we examined CYP1A2 above, the flavone inhibited the enzyme simply by virtue of having such complementary features to the binding site. It binds so tightly that it physically prevents other drugs from binding to it. Another way that a drug can inhibit CYP450 enzymes is by formation of a covalent bond that deactivates the active site. This happens with a well-known inhibitor of CYP3A4, <scene name='60/609993/Ritonavir/1'>ritonavir</scene>. Ritonavir is a HIV protease inhibitor routinely prescribed in combination with other antivirals. Its efficacy as part of a drug "cocktail" stems from the fact that it is a potent "irreversible inhibitor" of CYP3A4. Irreversible inhibition differs from most cases of competitive inhibition in that the enzyme is permanently deactivated, and must be re-synthesized by the cell. In contrast to erythromycin, there has been a covalent bond formed between the <scene name='60/609993/Ritonavir/3'>thiazole ring</scene> of the drug and the heme ring. Do you see how the thiazole has bound to the heme? | ||
In this case, we have taken advantage of the inhibition of CYP3A4 to prevent it from metabolizing the other antivirals of which ritonavir is co-administered. As you may expect though, extreme caution must be taken to prevent toxicity when other medications are taken concurrently. This is relatively easy to control when only one pharmacy is dispensing all of the medications a patient is prescribed. When more than one pharmacy is involved, however, serious interactions may be overlooked due to one pharmacy being unaware of the medications a patient is receiving from the other pharmacy. | In this case, we have taken advantage of the inhibition of CYP3A4 to prevent it from metabolizing the other antivirals of which ritonavir is co-administered. As you may expect though, extreme caution must be taken to prevent toxicity when other medications are taken concurrently. This is relatively easy to control when only one pharmacy is dispensing all of the medications a patient is prescribed. When more than one pharmacy is involved, however, serious interactions may be overlooked due to one pharmacy being unaware of the medications a patient is receiving from the other pharmacy. | ||
In the next section below, we will examine another factor that causes one drug to be metabolized by one CYP, while another might be metabolized by a second one. | In the next section below, we will examine another factor that causes one drug to be metabolized by one CYP, while another might be metabolized by a second one. | ||