Transcript
0:00What is metabolism?
Part three of our introduction to ADME: metabolism. Metabolism is the chemical change of a drug by enzymes, mainly in the liver. For about three quarters of the most prescribed drugs, it is the main route of elimination. Metabolism usually ends the action of the drug. It also usually makes the drug more water-soluble, so the kidneys can excrete the products in the urine, or the liver can excrete them in the bile. In some cases, metabolism activates a drug or forms a toxic product.
0:41Phase 1 and phase 2
Metabolism usually occurs in two phases. Phase 1 reactions add or expose a functional group, most often by oxidation. Cytochrome P450 enzymes, or CYPs, carry out most of these reactions. About a dozen CYPs metabolize 70 to 80 percent of the drugs in clinical use, and CYP3A4 alone carries out about a quarter of the CYP reactions with drugs. Phase 2 reactions join the drug, or its phase 1 metabolite, to an endogenous molecule, such as glucuronic acid, sulfate or glutathione. UDP-glucuronosyltransferases, or UGTs, sulfotransferases and glutathione S-transferases carry out these reactions. Most products are more water-soluble and inactive.
1:42First-pass metabolism
For an oral dose, metabolism starts before the drug reaches the systemic circulation. The drug reaches it only after it passes through the gut wall and the liver. Enzymes in the enterocytes, mainly CYP3A4, can metabolize part of the absorbed drug. Fg is the fraction of the absorbed drug that escapes metabolism in the gut wall. The portal vein then carries the drug to the liver. On this first passage through the liver, liver enzymes metabolize another part. This is hepatic first-pass metabolism. Fh is the fraction of the drug that passes through the liver unchanged. The oral bioavailability, F, is the fraction of the dose that reaches the systemic circulation unchanged. F is the product of Fa, Fg and Fh. Almost all of an oral dose of midazolam is absorbed. The gut wall then removes a little over 40 percent of the absorbed drug, and the liver removes a little over 40 percent of the rest, so F is only about 30 percent.
2:56Drug and food interactions
Other drugs and foods can change these enzymes. Grapefruit juice decreases the amount of CYP3A4 in the gut wall, and it increases the plasma concentrations of felodipine, an antihypertensive drug. Exposure is the plasma concentration of a drug added up over time. Ketoconazole and itraconazole inhibit CYP3A4: in one study, they increased the exposure to oral midazolam 10 to 15 times. Rifampicin induces CYP3A4: it increases the amount of the enzyme in the gut wall and the liver. In another study, rifampicin reduced the exposure to oral midazolam by 96 percent.
3:45Prodrugs
Metabolism can also activate a drug. Valacyclovir is a prodrug: it is hydrolyzed to the antiviral drug acyclovir, and 54 percent of an oral dose reaches the systemic circulation as acyclovir. CYP2D6 converts a small part of a dose of codeine into morphine, which is more active than codeine.
4:11Summary
In summary, metabolism is the main route of elimination for many drugs, and it usually ends their action. In the gut wall and the liver, it lowers the fraction of an oral dose that reaches the systemic circulation. Other drugs and foods change the enzymes, and prodrugs depend on them for their effect.
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Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.
