Transcript
0:00Prodrugs and active metabolites
Lesson 4.3 of our metabolism module: prodrugs and active metabolites. Metabolism is the chemical change of a drug by enzymes, proteins that make chemical reactions faster. Its product is a metabolite. Elimination is the irreversible loss of the drug from the body, by metabolism or by excretion in urine or bile. For many drugs, metabolism is the main route of elimination, and it usually ends the drug action. A prodrug is a compound with little or no activity of its own. In the body, an enzyme or a chemical reaction converts it to the active compound, the active metabolite. Chemists design many prodrugs to correct a poor property of the active compound, such as poor absorption. A drug with activity of its own can also form an active metabolite. In the ten years before 2018, the United States Food and Drug Administration approved at least 30 prodrugs. These made up more than 12 percent of the new small-molecule drugs. Four cases show how metabolism forms an active or a toxic compound.
1:29Valacyclovir
The first is valacyclovir, an antiviral prodrug. Hydrolysis activates it. In hydrolysis, water splits a chemical bond. Hydrolases, the enzymes of this reaction, activated about three quarters of the prodrugs in a review of United States drugs. Valacyclovir is acyclovir joined to the amino acid valine by an ester bond, a bond that water can split. Enzymes such as valacyclovir hydrolase split this bond and release acyclovir. The valine part lets PEPT1, a gut protein that carries small peptides, move the molecule across the gut wall. Oral bioavailability is the fraction of the dose that reaches the systemic circulation unchanged, through the gut wall and the liver. For valacyclovir, it counts the dose that arrives as acyclovir. Twelve healthy volunteers received valacyclovir by mouth and, as the 100 percent reference, acyclovir into a vein. The oral bioavailability of acyclovir from valacyclovir was 54.2 percent, three to five times the value for oral acyclovir. In a second study, four healthy volunteers took valacyclovir labeled with carbon-14, a radioactive form of carbon. Less than 0.5 percent of the dose appeared in urine as valacyclovir. More than 99 percent of the radioactivity in urine was acyclovir and its known metabolites. Almost all of the valacyclovir thus became acyclovir.
3:31Clopidogrel
The second is clopidogrel, a prodrug used to lower the risk of heart attack and stroke. Oxidation activates it. An oxidation usually adds an oxygen atom to a molecule. Carboxylesterase-1, a hydrolase, converts 85 percent of each dose to inactive acids. The other 15 percent is available for activation by two oxidation steps. Both steps need cytochrome P450 enzymes, or CYP enzymes, which oxidize many drugs in the liver. The first step forms 2-oxo-clopidogrel, and the second forms the active metabolite. In laboratory tests with single human enzymes, CYP2C19 contributed 44.9 percent of the first step and 20.6 percent of the second. CYP3A4 contributed the largest share of the second step, 39.8 percent. A loss of CYP2C19 activity can therefore lower both steps. Platelets are small cell fragments in the blood. Their attachment to each other, platelet aggregation, helps to form a clot. Only the active metabolite blocks P2Y12, a receptor on platelets, and the block lowers platelet aggregation. The block is irreversible, so the receptor stays blocked for the life of the platelet, about 10 days.
5:15CYP2C19 and the clopidogrel response
One study tested whether a weaker activation step lowers the effect of clopidogrel. An allele is one version of a gene, and each person carries two copies of most genes, one from each parent. A reduced-function allele of CYP2C19 lowers the enzyme activity. Among 162 healthy volunteers who took clopidogrel, about 30 percent carried at least one such allele. Exposure is the AUC, the area under the curve of drug concentration in plasma, the liquid part of the blood, against time. The carriers had a 32.4 percent lower exposure to the active metabolite than the other volunteers. The drop in platelet aggregation with clopidogrel was 9 percentage points smaller in the carriers. Carriers thus had less active metabolite and a smaller effect on their platelets. The same report covered 1,477 patients who took clopidogrel after an acute coronary syndrome, a sudden fall in blood flow to the heart muscle. Cardiovascular death, heart attack or stroke occurred in 12.1 percent of carriers, against 8.0 percent of the other patients.
6:49Codeine
The third is codeine, a drug with weak activity of its own. CYP2D6 converts a small part of each dose to morphine, and morphine produces most of the pain relief.
7:04Paracetamol
The fourth is paracetamol, a drug for pain and fever. It forms a toxic metabolite. At a therapeutic dose, CYP enzymes oxidize 5 to 10 percent of the dose to this metabolite, NAPQI. Glutathione, a small peptide, binds NAPQI and makes it harmless. After a highly toxic dose, more than 15 percent forms NAPQI, and the glutathione in the liver falls. The NAPQI that remains free can then kill liver cells. In summary, a prodrug has little or no activity until the body converts it to an active metabolite.
7:51Summary
Hydrolysis releases acyclovir from valacyclovir. Two CYP oxidation steps activate clopidogrel. Healthy carriers of a reduced-function CYP2C19 allele had 32.4 percent less exposure to the active metabolite. Among patients who took clopidogrel after an acute coronary syndrome, carriers had a higher rate of cardiovascular death, heart attack or stroke. Codeine acts mainly through morphine, which CYP2D6 forms from a small part of each dose. Paracetamol forms the toxic metabolite NAPQI, which can kill liver cells after a highly toxic dose. A change in the enzyme that forms an active metabolite can change the drug effect. This concludes lesson 4.3 on prodrugs and active metabolites.
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Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.
