Some 24-hour rhythms of the body are well known, starting with the sleep-wake cycle itself. But scientists at the University of Pennsylvania have shown that at the molecular level, such daily rhythms are extremely common.

In genes that are the targets of known drugs, in fact, they are more common than not. When the team looked at daily rhythms of the genes targeted by the 100 bestselling drugs in the U.S., the majority of those genes showed a daily oscillation in at least one of the 12 sites the scientists looked at.

Not all of those circadian rhythms will matter in practice. Acute myeloid leukemia drug Neulasta (pegfilgrastim, Amgen Inc.), for example, targets the gene Csf3r, which showed a circadian rhythm in the lung.

But overall, senior author John Hogenesch of the University of Pennsylvania told BioWorld Today, "the degree to which the targetable genome is clock-regulated was a big surprise."

Hogenesch said he thinks a quarter to half of the circadian fluctuations his team identified, which appeared in the Oct 27, 2014, online edition of the Proceedings of the National Academy of Sciences, could end up being clinically relevant.

That there is a genetically controlled circadian clock has long been clear: that circadian rhythm is controlled by the suprachiasmatic nucleus, a part of the hypothalamus that receives input from the retina and whose activity is controlled by the amount of light the retina is sensing.

In their work, the team looked at 12 separate sites, including the hypothalamus itself, as well as two other brain sites, lungs, liver, brown and white fat, and others.

They used two different ways to quantify gene expression levels. Microarray data collected every two hours "were focused entirely on protein-coding genes," while RNA-seq data every six hours rounded out the picture with noncoding genes and splice variants. Using those methods, the authors found that 43 percent of the genes they looked at showed circadian fluctuations in at least one organ. The percentage of genes that showed such changes ranged from a high of 16 percent in the liver, to a low of 3 percent in the hypothalamus.

The fact that the hypothalamus, which is itself the site of the master circadian clock, should rank dead last in such a survey was surprising to the team. In fact, of the 12 sites in 10 organs that the authors looked at, all three brain regions – the hypothalamus, cerebellum and brainstem – occupied the bottom three spots.

Hogenesch noted that his team does not quite trust those data. The brain has many cell types, and those cell types may be out of sync with each other, making different rhythms ion different cell types look like no rhythm in the overall sampling.

Another surprising result was that many organs were not simply biphasic, alternating periods of high activity and rest. Instead, Hogenesch said, there were two "rush hour" periods of high activity that preceded changes from light to dark and vice versa.

Hogenesch said he was less surprised by the finding that genes targeted by drugs were especially likely to show circadian expression rhythms. The reason may lie in their biology – good drug targets are often genes with regulatory functions, which would be expected to have a circadian rhythm.

Those findings do have practical implications for both clinical practice and clinical trials – specifically, Hogenesch said, that "it's important to keep time in mind." That goes both for the time that pills are taken, and, in clinical trials, the time that physical measures are evaluated.

In the paper, the team pointed out that more than half of the 100 top-selling drugs in the U.S. have half-lives of less than six hours. Those drugs are likely to encounter significantly different amounts of their targets depending on when they are administered.

For a select few drugs, that relationship is widely known. Some of those are obvious; for example, a patient takes a sleeping pill at bedtime. Others are less obvious but still well known. Statins, for example, work best in the evening because cholesterol synthesis peaks at night, to compensate for the fact that there is no dietary intake.

But in general, most doctors, including those running clinical trials, don't pay much attention to the time of day that patients take their pills. The new findings suggest that they should.