Redesigning Drugs For Better Breakdown In The Environment | Chemical & Engineering News
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Web Date: September 4, 2015

Redesigning Drugs For Better Breakdown In The Environment

Environment: Researchers fine-tune a common cardiovascular drug to improve its biodegradability in wastewater
Department: Science & Technology
News Channels: Environmental SCENE, Organic SCENE
Keywords: micropollutants, pharmaceuticals, wastewater, drug design, beta blockers, propranolol, biodegradability

When pharmaceuticals go down the drain—often in people’s waste—they can persist through wastewater treatment, reaching waterways and posing harm to fish and other aquatic creatures. Researchers have been working on ways to remove these micropollutants from wastewater, and now one team introduces a new approach: design replacement drugs that biodegrade once they reach the environment. The researchers modified a drug commonly used to treat high blood pressure into a form that should still be pharmacologically active but that breaks down more easily in wastewater treatment (Environ. Sci. Technol. 2015, DOI: 10.1021/acs.est.5b03051).

Klaus Kümmerer of Leuphana University of Lüneburg, in Germany, came up with the idea while testing methods to remove micropollutants from wastewater. One method is exposure to ultraviolet light, which can transform compounds into more biodegradable products. He realized that this approach might also be used to synthesize more biodegradable alternatives to current drugs.

So he and his team tested the idea on propranolol, a beta blocker used to treat high blood pressure. Propranolol is toxic to some aquatic creatures when they’re chronically exposed at concentrations found in wastewater effluent, and the drug does not biodegrade in the environment. The researchers first dissolved the drug in pure water and exposed it to UV light for about four hours, yielding 16 derivatives that they identified using liquid chromatography with tandem mass spectrometry. Then they tested these compounds’ biodegradability by incubating them with effluent from a local sewage treatment plant and measuring consumption of oxygen and organic carbon over time by the microbes present.

BETTER BLOCKER?
Caption Body: Researchers tweaked propranolol (left), a common beta blocker used to treat high blood pressure, into a more biodegradable alternative, 4-hydroxypropranolol (right).

They found that the most biodegradable derivatives were hydroxylated on one of propranolol’s aromatic rings. This change makes the ring more likely to open up, allowing easier access for microbes to digest the drug. The most promising derivative, 4-hydroxypropranolol, biodegraded by 23% into inorganic components such as carbon dioxide and water after one month. Some 48% of the derivative was at least partially degraded into other organic compounds that computer models predict to be low in toxicity.

Using computer modeling and a cell culture binding assay, the researchers predicted that 4-hydroxypropranolol should have similar drug activity to propranolol, as well as low toxicity and good absorption. These findings are corroborated by an earlier study showing that the two compounds have similar activity in rats, cats, dogs, and guinea pigs.

Kümmerer says the photochemical approach could be used to explore biodegradable alternatives for most drugs and other micropollutants, such as those found in personal care products. He and his team hope to improve the biodegradability of the propranolol derivative, and to investigate other methods to enhance drug decomposition.

“I’m overwhelmed with the innovativeness of the idea,” says Susan D. Richardson, an environmental chemist at the University of South Carolina. She says the researchers have cleverly used a simple method to produce an alternative compound with promising biodegradability.

For their next steps, she says the researchers should study the toxicity of the derivative and its degradation products in living organisms. They should also test whether drinking water treatment, such as chlorination, would transform these compounds into toxic by-products. If these hurdles are cleared, she says, this method “could be a revolutionary way to lower our load of drugs to the environment.”

 
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Comments
Jay Spivack (September 5, 2015 1:19 PM)
It seems to me that the largest hurdle any such compound must pass isn't mentioned here. Will it be an effective drug? The lengthy and expensive road of animal and then clinical trials lies ahead. Who will pay for it?

It also seems reasonable to expect that the more biodegradable the compound the more likely it will be rapidly metabolized in humans. This could lead to inconveniently short half-lives in humans.

The basic idea: drugs that readily degrade in the environment is excellent. This method, which more or less randomly changes the structures of existing drugs does not seem the to be the most efficient way to accomplish the goal. Perhaps the best route is to convince (or regulate) the pharmaceutical companies to include environmental degradation in their initial design and screening of new drugs.
Graeme Dykes (September 9, 2015 3:15 PM)
This is an interesting test case but raises a number of concerns. In many cases medicinal chemist work hard to limit too rapid metabolism and clearance.
It may not be sufficient to consider only the toxicity of the pharmaceutical, (propranolol, in this case). One should consider how the parent drug is metabolised in patients and what proportion is excreted unchanged and what metabolites are formed. It would not be unreasonable to expect that 4-hydroxpropranolol is a product of normal metabolism
Metabolites of a number of pharmaceuticals have been shown to have activity also against the primary target.
The nature of the target disease should also be part of the assessment. For example, adding a further H-bond donor to a CNS drug, may severely limit passage across the blood brain barrier.
In this particular case medicinal chemists may be wary of incorporating such phenol moieties. Such functional groups have an increased tendency to form reactive and often toxic metabolites. It would be valuable to show that 4-hydroxpropranolol is activated towards degradation by UV irradiation and not also by normal metabolic enzymes. Otherwise, in vivo toxicity may limit further development of this example and limit the scope of the approach.
Robert Galemmo (September 9, 2015 9:56 PM)
Unfortunately, the addition of the aryl hydroxyl group and it's position on the naphthyl ring makes it an excellent substrate for microsome oxidation and would also provide a nice handle for phase 2 conjugation processes (glucuronidation, sulfonation etc...). It's likely to be more rapidly cleared in vivo. While conceptually this is an interesting approach, it is also highly likely that the modifications that make a drug degradable in the environment will also adversely impact metabolic stability as well.

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