Time taken can affect prescription efficacy

For some of the most common drugs in U.S. medicine cabinets, the time of day they are taken can determine how well they work.

That is the conclusion of University of Pennsylvania scientists, who based their finding on an exhaustive, hour-by-hour analysis of the internal protein-generating machinery in mice.

Of the nearly 20,000 mouse genes known to contain recipes for making proteins, 43 percent were found to have a clocklike, "circadian" quality, revving up or slowing down their activity level at specific times every day. Almost all of these genes have close equivalents in humans.

And of the 100 top-selling drugs in the United States, 56 target the product of one of these circadian genes, the authors reported recently in Proceedings of the National Academy of Sciences.

So, the thinking goes, if you are taking a drug designed to interact with a certain type of protein in your body, you would want to take it when a lot of that protein is being made. That is especially true if the drug has a short half-life, meaning it is eliminated quickly from the body.

While the clock-sensitive nature of several drug targets on the list was previously known, in most cases it was not, said the study's senior author, John Hogenesch, a professor at Penn's Perelman School of Medicine. He and his coauthors stopped short of proving that these drugs should be taken at certain times, but already were developing hypotheses to test just that.

"If they do have time-of-day effects, there's the potential to make these medications work better by taking them at the right time," said Hogenesch, a neuroscientist.

Among those on the list that were previously known to be more effective at night were short-acting statins and low-dose aspirin - the latter when the goal is lowering blood pressure. (Aspirin's anticlotting ability is consistent throughout the day.)

But certain beta-blockers, when taken at night, can interfere with the body's production of melatonin and thereby with sleep, Hogenesch said. The beta-blockers in question are those that penetrate the blood-brain barrier, such as Toprol, he said. One possible solution, studied by other researchers, is for the patient to take melatonin supplements.

As for the drugs that were not previously known to have targets that rise and fall with the time of day, the list identified by the Penn team included acid reflux medicines such as Nexium; the antiviral drug Tamiflu; Seroquel, prescribed for bipolar disorder and depression; Rituxan, used to treat rheumatoid arthritis and non-Hodgkin's lymphoma; and certain hypertension and asthma medicines.

"Right now, we're kicking around several ideas for testing medicines at particular times of day," Hogenesch said. "We have a general sense of within three or four hours for when certain things should be taken."

A spokesperson for AstraZeneca, which makes Seroquel, Nexium, and Toprol, said the company could not comment on the study, but was confident in its products' safety and efficacy when used as indicated. Genentech, which makes Tamiflu and Rituxan, declined to comment, saying it needed more time to review the findings.

Hogenesch said the circadian nature of the various mouse genes almost certainly was present in their human counterparts, as 99 percent of the animal's genes have human equivalents. Plus, that scenario fits with the understanding of the few drugs known to work better at certain times.

The study could prove useful not just in pointing the way toward better drug efficacy, but also toward reducing side effects, said biologist Satchin Panda, an associate professor at the Salk Institute for Biological Studies in La Jolla, Calif.

"Can we actually get away with lesser amounts of drugs?" asked Panda, who has worked with Hogenesch on past research, but was not involved in this study. "Nobody wants to put too much drugs in our systems."

The Penn scientists, who were joined by a University of Missouri researcher, looked at the activity of the clock-dependent genes and the organs in which the corresponding proteins were expressed. Most of them oscillated in just one or two organs.

For drugs on the list that were previously known to work better at certain times, the authors fleshed out that knowledge by analyzing why that might be true.

The bottom line, Hogenesch said, is that the study contains a rough road map for getting more out of existing medicines. It could be as simple as watching the clock.

"It's a lot faster and a lot easier to do than coming up with the drugs in the first place," he said. "We already know that they're safe and efficacious. We're just trying to make them a little bit better."

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