As a particular concern in drug binding to erythrocytes, circadian time-dependent changes in the passage of drug into erythrocytes have been demonstrated for drugs such as local anesthetics, indomethacine, and theophylline. Circadian rhythm can affect blood flow in liver and thus, can affect the clearance of several drugs, including propranolol. In mammals, most of the xenobiotics are metabolized in mainly in liver. However, there is also extrahepatic metabolism in brain, kidney, lung and other tissues.
Xenobiotic metabolism is composed of three groups of proteins with distinct functions.
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After phase II reactions, the xenobiotic conjugates may be further metabolized in phase III reactions. Variations of several oxidative reactions catalyzed by the CYP enzymes been reported for substrates such as aminopyrine, paranitroanisole, hexobarbital and 4-dimethyaminobenzene, aniline, benzphetamine, benzpyrene and imipramine. Conversely, sulfate conjugations are much faster during rest than during activity. Here we should also mention peroxisome proliferator-activated receptors PPAR , particularly alpha. It can be suggested that the central circadian clock components and PPARs exhibit a reciprocal regulation.
This imbalance is known to attribute to metabolic syndrome, a complex disease with distinct hallmarks including obesity, dyslipidemia, hypertension, and elevated plasma glucose level. The circadian timing system plays a key role in the changes of toxicity of drugs by influencing their metabolisms in the liver and intestine in addition to their excretion via bile flow and urine.
Rats with chronic biliary drainage under a rigid lighting schedule light on at 6 am and off at 6 pm exhibited a remarkable circadian rhythm of bile flow, biliary concentrations and excretory rates of bile salts, cholesterol and phospholipids. Several variables influencing pharmacokinetics i. Particularly, the time of administration should be controlled in order to prevent variations in drug pharmacokinetics. Clinical pharmacists and pharmacy practitioners should take into account that the application time may be as important as the dose and route for certain drugs, particularly for those that has a narrow therapeutic range.
If the symptoms of a disease are distinctly circadian phase-dependent like symptoms of myocardial infarction, angina pectoris, nocturnal asthma, peptic ulcer , pharmacists should also warn the patients for the correct time of administration of the drug used for the treatment of such disease. For example, in asthma patients, as lung function undergoes circadian changes and reaches to a low point in the morning hours, chronotherapy for asthma should be aimed at getting maximal effect from bronchodilators during early morning hours.
As gastric secretion reaches to its highest at night, chronotherapy for peptic ulsers should be at evening, with once daily H 2 -receptor antagonists like ranitidine, famotidine. Rheumatoid arthritis symptoms are usually intense on awakening and NSAIDs should be administered in morning and noon times due to the symptom timing of this disease.
Biological Rhythms and Medicine
Cardiovascular diseases like hypertension, heart attack and stroke mostly occurs in morning time as blood pressure is at its lowest at night time and makes a steep rise in the awakening period. Therefore, medications curing such diseases should be preferably administered at morning time. It is known that chronobiological cycles for normal cells and cancer cells are different. Blood flow to tumors and tumor growth rate are greater during activity phase than rest phase and usually midnight therapy was shown to be more effective.
A right choice for the time of administration of cancer drugs should be made after observing the cell cycle changes of the cancer cells in the patients. Circadian rhythms have an important impact on drug effectiveness and toxicity. Chronopharmacology aims to improve the understanding of circadian changes in both desired effects chronoeffectiveness and tolerance chronotolerance of medications.
Besides, the efficiency of pharmacotherapy can be enhanced by administering drugs at times during which they are best tolerated. These medications can identify the proper dosing time and this amelioration will lead to improved progress and diffusion of pharmacotherapy. Both authors contributed the idea of paper and the manuscript preparation. Source of Support: Nil. Conflict of Interest: The authors declare no conflicts of interest.
This article has been cited by other articles in PMC. Abstract A rough hour cycle driven endogenously in biochemical, physiological or behavioral processes is called circadian rhythm. Keywords: Absorption, circadian rhythm, chronopharmacology, chronocokinetics, distribution, excretion, metabolism. Circadian rhythms in distribution In biological fluids and tissues, circadian changes related to drug distribution are shown to change according to time of day.
Circadian rhythms in excretion The circadian timing system plays a key role in the changes of toxicity of drugs by influencing their metabolisms in the liver and intestine in addition to their excretion via bile flow and urine. Gehring W, Rosbash M. The coevolution of bluelight photoreception and circadian rhythms. J Mol Evol. Does the clock make the poison?
Circadian variation in response to pesticides.
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A web of circadian pacemakers. Induction of circadian rhythm in cultured human mesenchymal stem cells by serum shock and cAMP analogs in vitro.
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Crayfish Procambarus clarkii shows Circadian Variations in Different Parameters of the GSH Cycle¶
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Anthony M, Berg MJ. Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics: Part II. Physiopathological alterations of alpha 1 acid glycoprotein temporal variations: Implications for chronopharmacology.