Sandbox CYPMetabolism: Difference between revisions
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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. | |||
== Active site Volume Affects Drug Selectivity== | |||
Some of the factors that determine which particular CYP450 isoform metabolizes a given drug is the shape and size of its active site. As we saw above, induced fit can cause the shape of a binding pocket to change. However, induced fit may not be enough to allow a CYP with a small binding pocket to open up enough to allow larger drugs to bind. The windows below show two CYP450 isoforms with very different selectivity. The first is the structure of CYP2E1, bound to the enzyme inhibitor 4-methylpyrazole (PDB code [[3e4e]]). The second is the structure of CYP3A4 bound to the inhibitor erythromycin ([[2j0d]]). Make sure that the check box below the second window is checked. Now rotate and re-size the structures until you can see the heme group and the size and shape of the active site. | |||
Use one of the buttons below each applet to toggle the transparency of the active site in the CYP2E1 structure and the CYP3A4 structure until you can see how the substrate is bound relative to the heme. If you need to, you can reset the molecules to their original orientation using the other button below the interactive window. | |||
Notice the size of the active site in the CYP2E1 structure relative to that of the CYP3A4 structure. Although the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small, such as ethanol, halothane, and aniline. On the opposite end of the spectrum, CYP3A4 can accommodate drugs that are quite large. | |||