Ana Luisa Robles-Piedras^*, Urias Bautista-Sánchez, Elena Guadalupe Olvera-Hernández and Alejandro Chehue-Romero

Universidad Autónoma del Estado de Hidalgo, Instituto de Ciencias de la Salud, Área Académica de Farmacia, San Agustín Tlaxiaca, Hidalgo. México

Corresponding Author E-mail:roblesa@uaeh.edu.mx

Abstract

Chronopharmacokinetics is a specialized field within pharmacokinetics that focuses on how the timing of drug administration affects the absorption, distribution, metabolism, and elimination of drugs. The circadian rhythm, governed by the body's biological clock, plays a crucial role in pharmacokinetics, which encompasses the absorption, distribution, metabolism, and elimination of drugs. These pharmacokinetic processes are subject to daily variations influenced by the circadian rhythm. Drug absorption can fluctuate due to changes in gastrointestinal function, such as motility and gastric pH, and blood circulation. Similarly, the distribution of drugs in the body is influenced by factors such as tissue perfusion, plasma protein binding, and cell membrane permeability, all of which are modulated by the circadian rhythm. Metabolism, especially hepatic metabolism, can also experience circadian variations that affect the rate at which drugs are processed and converted into active or inactive metabolites. Finally, the elimination of drugs, primarily through renal function, can show circadian rhythms that impact the excretion of compounds from the body. Understanding these circadian fluctuations is essential to optimize the efficacy and safety of pharmacological treatments, as dosages and administration times could be adjusted to align with the peaks of biological clock activity. Thus, treatments can be more effective and have fewer side effects by leveraging the circadian variability in pharmacokinetic processes.

Keywords

Circadian rhythm; Drugs; Efficacy; Pharmacokinetics

Copy the following to cite this article: Piedras A. L. R, Sánchez U. B, Hernández E. G. O, Romero A. C. Chronopharmacokinetics: A Brief Analysis of the Influence of Circadian Rhythm on the Absorption, Distribution, Metabolism, and Elimination of Drugs. Biomed Pharmacol J 2024;17(3).

Copy the following to cite this URL: Piedras A. L. R, Sánchez U. B, Hernández E. G. O, Romero A. C. Chronopharmacokinetics: A Brief Analysis of the Influence of Circadian Rhythm on the Absorption, Distribution, Metabolism, and Elimination of Drugs. Biomed Pharmacol J 2024;17(3). Available from: https://bit.ly/3XtMc4F

Introduction

Chronopharmacokinetics is a specialized field within pharmacokinetics that focuses on how the timing of drug administration affects the absorption, distribution, metabolism, and elimination of drugs. It takes into account the body’s biological rhythms, particularly circadian rhythms, to optimize drug therapy by aligning it with these natural cycles¹.

Chronopharmacokinetics is an emerging and increasingly significant field within pharmacology that studies how the timing of drug administration influences pharmacokinetics (how drugs are absorbed, distributed, metabolized, and eliminated by the body). This field recognizes that physiological and metabolic processes in the body exhibit predictable fluctuations according to the circadian rhythm, the internal clock that governs various biological functions over a 24-hour period. Understanding these fluctuations is essential as they can profoundly affect the pharmacokinetics of drugs, impacting both their efficacy and safety^1,2. The primary aim of chronopharmacokinetics is to optimize pharmacological treatments by aligning drug administration with the body’s natural rhythms. This synchronization can maximize therapeutic benefits while minimizing side effects and associated risks. By tailoring medication schedules to fit individual circadian rhythms, healthcare providers can enhance the effectiveness of treatments and reduce toxicity, leading to more personalized and efficient patient care³.

The implications of chronopharmacokinetics extend to various fields, including precision medicine, oncology, cardiology, and the treatment of sleep disorders, among others. For a comprehensive understanding of how circadian rhythms impact pharmacokinetics, it is necessary to examine each stage of the pharmacokinetic process and how each is affected by biological rhythms. This includes the drug’s absorption from its dosage form, its distribution to tissues or binding to proteins, its metabolism or chemical transformation, and finally, its elimination from the body^4,5.

Pharmacokinetics process.

Absorption

Drug absorption is a critical phase in pharmacokinetics, involving the movement of a drug from the site of administration into the systemic circulation. The extent and rate of absorption are crucial for determining the drug’s bioavailability, or the proportion of the drug that reaches the bloodstream in an active form. Factors such as gastrointestinal (GI) motility, blood flow, and the presence of food can significantly influence absorption².

The body’s circadian rhythm affects various aspects of GI function, including motility and blood perfusion. For instance, gastrointestinal motility, which is the ability of the digestive system to move its contents through the GI tract, can vary throughout the day. This variation can impact the time a drug remains in the absorption site and, consequently, the extent of its absorption. Similarly, intestinal blood perfusion, which is the blood flow through the intestinal blood vessels, fluctuates over the day, affecting the drug’s absorption rate. Circadian rhythms also influence the expression of membrane transporters and metabolic enzymes in the intestine¹.

Membrane transporters are proteins that facilitate the transit of substances across cell membranes, and metabolic enzymes are responsible for breaking down and metabolizing drugs. These proteins’ expression levels can vary according to the time of day, thereby affecting the absorption of certain drugs. For example, the permeability of the intestinal barrier and the activity of transport proteins can change, altering the amount of drug that enters the systemic circulation^6,7.

Distribution

The distribution phase of pharmacokinetics involves the transportation of a drug from the bloodstream to various tissues and organs. This process determines where and how the drug exerts its therapeutic effects in the body. Several factors influence drug distribution, including tissue perfusion, plasma protein binding, and cell membrane permeability¹. Tissue perfusion, the blood supply to tissues and organs, can vary with circadian rhythms due to changes in physical activity and metabolic rates. For instance, during periods of rest, blood flow to certain organs may decrease, while during active periods, it may increase, affecting the amount of drug that reaches specific tissues. This variation can impact the drug’s effectiveness and duration of action. Plasma protein binding is another critical factor in drug distribution. Many drugs bind to proteins in the blood, such as albumin, which affects the free (unbound) drug concentration available to exert therapeutic effects⁴. The formation of drug-protein complexes can fluctuate throughout the day due to circadian changes in protein levels¹. Higher or lower protein levels can influence how much of the drug is available in its active form. Additionally, cell membrane permeability, which controls the entry and exit of substances in and out of cells, can vary over the course of the day. Changes in cellular activity and metabolic rates can alter membrane permeability, influencing the distribution of drugs across different tissues^4,6. 

Metabolism

Drug metabolism is a complex and essential pharmacokinetic process involving the chemical alteration of drugs into forms that can be more easily eliminated from the body. This process not only converts drugs into active or inactive metabolites but also makes them more water-soluble to facilitate excretion². The liver plays a central role in drug metabolism, primarily through the activity of metabolic enzymes. The cytochrome P450 (CYP) enzyme system, particularly significant within the liver, contains multiple enzymes that catalyze the oxidation of many drugs. These enzymes prepare drugs for elimination from the body. Various factors, including genetics, health status, and the presence of other drugs, can affect enzyme activity. For instance, some drugs may inhibit or induce the activity of specific CYP enzymes, altering the metabolism of concurrently administered medications¹.

Circadian rhythms can influence the activity of these metabolic enzymes. Research has shown that certain CYP enzymes, such as CYP3A4, exhibit circadian patterns in their activity. For example, CYP3A4 tends to be more active at night, suggesting that drugs metabolized by this enzyme may be processed differently depending on the time of administration⁴. These circadian variations in enzyme activity have significant clinical implications, potentially affecting drug dosage and timing to enhance efficacy and reduce side effects. Furthermore, interactions between different drugs can modify metabolism.

Drugs that inhibit CYP enzymes can increase the concentration of another drug by decreasing its metabolism, leading to potential toxicity. Conversely, drugs that induce CYP enzymes can reduce the concentration of another drug by accelerating its metabolism, potentially decreasing its therapeutic effectiveness. Understanding these interactions is crucial to avoid adverse effects and ensure patient safety^1,7.

Elimination

Drug elimination is the final phase of pharmacokinetics, involving the removal of the drug from the body and the termination of its pharmacological effects. The primary organs responsible for drug elimination are the kidneys and the liver. Drugs are primarily excreted through urine (via the kidneys) and bile (via the liver). The rate of drug elimination is influenced by factors such as urinary flow and renal function. High urinary flow can accelerate drug elimination, while impaired renal function can lead to the accumulation of drugs, increasing the risk of toxicity^1,3.

Renal function itself is subject to circadian rhythms, with glomerular filtration rate and renal blood flow varying throughout the day. These fluctuations can affect the elimination of drugs excreted predominantly by the kidneys. Biliary secretion also plays a crucial role in drug elimination. Some drugs and their metabolites are excreted into the bile and subsequently eliminated with feces. Like renal function, bile secretion is influenced by circadian rhythms. The efficiency of bile excretion can vary, affecting the elimination rate of drugs processed through this route^8-10.

To further understand the impact of circadian rhythms on pharmacokinetic processes, including absorption, distribution, metabolism, and elimination, refer to Table 1. This table provides a summarized overview of how circadian rhythms influence these processes and the bioavailability of drugs. This understanding can enhance the optimization of drug therapy by aligning medication schedules with the body’s natural rhythms.

Table 1: Circadian rhythm and their effects on pharmacokinetic processes.

Pharmacokinetic process	Change in circadian rhythm	References
Absorption	Gastric pH: Varies throughout the day, affecting the solubility of acidic and basic drugs, with peaks of acidity at night. Gastrointestinal motility: Is faster in the morning, which favors drug absorption, while it slows down at night. Intestinal blood flow: Fluctuates with peaks during the active hours of the day, improving absorption during these times. Interaction with food: Absorption can vary depending on the presence of food, which follows a circadian rhythm based on meal times.	3, 11, 12, 13
Distribution	Albumin levels: Plasma levels of albumin and other binding proteins vary throughout the day, affecting the free fraction of drugs. Tissue perfusion: Circadian variations in tissue blood flow influence drug distribution, with greater perfusion during the day. Volume of distribution: Changes with hydration status and vascular tone, which are modulated by the circadian rhythm. Transport and cellular penetration: The expression of membrane transporters and cellular penetration proteins can follow a circadian rhythm, affecting the intracellular distribution of drugs.	14, 15, 12, 16
Metabolism	Hepatic enzyme activity: Enzymes, including those in the cytochrome P450 family, exhibit circadian rhythms, with peak activity typically occurring at night or early morning, which influences the rate of drug metabolism. Gene expression: The circadian clock can regulate the genes involved in drug metabolism, leading to variations in their expression and activity at different times of the day. Hormonal fluctuations: Metabolic enzyme activity is affected by hormones like cortisol, which follow a circadian rhythm. Interactions with other drugs: Administering multiple drugs at various times of the day can lead to pharmacokinetic interactions due to circadian changes in metabolism.	17, 18,19, 20
Excretion	Glomerular filtration rate (GFR): Shows circadian variations, generally being higher during the day, which affects the renal elimination of drugs. Urine flow: Diurnal fluctuations in urine flow can influence the concentration and excretion of drugs and their metabolites, with greater excretion during active hours. Tubular secretion: Can vary depending on the time of day, modifying the elimination of drugs that rely on this mechanism. Variations in urinary pH: The pH of urine changes throughout the day, affecting the solubility and excretion of certain drugs.	9, 21, 22, 23, 24
Bioavailability	The bioavailability of a drug can be affected by the time of day due to the interaction of changes in absorption, distribution, metabolism, and excretion. Influence of the sleep-wake cycle: Sleep and wake patterns can influence pharmacokinetics, altering bioavailability. Drug-receptor interactions: The sensitivity of receptors to drugs can vary according to the circadian rhythm, affecting therapeutic efficacy. Influence of food and beverages: Bioavailability can vary depending on the time of day and the type of food or beverages consumed.	12, 25, 26, 27

 

Chronopharmacokinetics, an emerging area.

Several studies have highlighted the significance of circadian timing in optimizing drug efficacy, minimizing adverse effects, and advancing therapeutic strategies, particularly in the treatment of neurological disorders, psychiatric conditions, and chronic diseases such as hypertension and diabetes^28,29. On the one hand, it has been studied the critical role of circadian rhythms in modulating neuropsychiatric adverse reactions, particularly in relation to the timing of drug administration^30,31. In 2014, a study was carried out to investigate the impact of circadian timing on neuropsychiatric symptoms during a Phase I clinical trial involving metabotropic glutamate receptor 5 (mGluR5) modulation, finding that adverse effects like hallucinations varied significantly based on the time of drug administration³⁰. Similarly, in 2018 were examined the effects of circadian rhythms on mood and cognitive function in patients with bipolar disorder³¹. They discovered that aligning medication with patients’ circadian rhythms reduced the severity of mood swings and cognitive disturbances. These studies underscore the importance of circadian timing in psychopharmacology, suggesting that optimizing drug administration schedules to align with biological rhythms can minimize adverse effects and improve therapeutic outcomes in neuropsychiatric treatments. Likewise, other researchers³² delved into the broader implications of circadian rhythms on drug metabolism and detoxification, emphasizing the role of the circadian timing system (CTS) in regulating hepatic enzyme activity, particularly the cytochrome P450 (CYP) enzymes. This study highlights that the activity of these enzymes fluctuates throughout the day, which can significantly influence drug metabolism. For instance, the hepatic CYP3A4 enzyme, responsible for metabolizing a large proportion of drugs, exhibits circadian variations in its activity. This has profound implications for drug dosing and timing, as administering a drug when its metabolizing enzyme is less active could lead to higher drug concentrations, increasing the risk of toxicity. Conversely, dosing during peak enzyme activity could result in faster drug clearance, potentially reducing therapeutic efficacy. This understanding emphasizes the need for chronopharmacokinetic studies during drug development and clinical trials to optimize dosing schedules according to the CTS, thereby enhancing drug safety and efficacy. Recently other researchers,build on the concept of CTS, by advocating for the integration of chronopharmacokinetics into the drug discovery and development process³³. They argue that the traditional approach to pharmacokinetics, which often neglects the timing of drug administration, may overlook critical factors that influence drug efficacy and safety. By incorporating chronopharmacokinetics into early-stage drug development, researchers can design drugs that are more aligned with the body’s circadian rhythms, potentially reducing the incidence of adverse effects and improving therapeutic outcomes. The authors suggest that this approach could be particularly beneficial in developing drugs for chronic conditions like hypertension and diabetes, where the timing of drug administration could significantly impact disease management and patient outcomes.

Also, other authors offer a practical application of chronopharmacokinetics in the treatment of epilepsy, a neurological disorder characterized by rhythmic seizures that often follow a circadian pattern³⁴. Their research highlights the potential of chronomodulated therapy, where antiepileptic drugs are administered in sync with the patient’s circadian rhythms, to optimize seizure control and minimize side effects. The study demonstrates that seizures are more likely to occur at specific times of the day, and by timing drug administration to these periods, clinicians can enhance the drug’s therapeutic effect while reducing the likelihood of adverse reactions. This approach not only improves patient outcomes but also underscores the importance of personalized medicine, where treatment is tailored to the individual’s biological rhythms. On the other hand, recent studies explore the technological advancements in controlled-release drug delivery systems designed for chronotherapy³⁵. These systems are engineered to release medication at specific times, aligning with the body’s circadian rhythms. For example, in the management of hypertension, where blood pressure typically surges in the early morning, controlled-release formulations can be designed to release antihypertensive drugs just before this surge, thereby preventing cardiovascular events and improving blood pressure control. The authors emphasize that such technologies represent a significant step forward in the development of chronotherapeutic strategies, offering the potential to enhance drug efficacy and patient adherence, particularly in the treatment of chronic conditions that follow a circadian pattern.

Conclusion

Chronopharmacokinetics offers profound insights into the relationship between drug administration timing and pharmacokinetic processes. Research has demonstrated that the timing of medication administration can significantly influence treatment efficacy and safety. The studies reviewed highlight the importance of considering the timing of drug administration in relation to the body’s circadian rhythms, particularly in the treatment of neurological disorders, psychiatric conditions, and chronic diseases like hypertension and diabetes. Studies have shown that administering antihypertensive drugs like angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor blockers (ARBs) at night can lead to greater reductions in blood pressure and a lower incidence of cardiovascular events compared to morning administration^1,3. In oncology, the timing of chemotherapy has been found to affect treatment outcomes. Administering chemotherapy at specific times of the day can improve drug tolerance and efficacy in cancer patients. This is because the body’s circadian rhythms can influence the metabolism and elimination of chemotherapeutic agents, affecting their toxicity and therapeutic index⁴. Understanding circadian rhythms is essential in clinical practice for determining the optimal timing for drug administration, maximizing therapeutic benefits while minimizing side effects. This knowledge is particularly relevant for drugs with narrow therapeutic windows, where fluctuations in plasma levels can have critical consequences. By integrating chronopharmacokinetics into clinical decision-making, health professionals can tailor treatment regimens to align with patients’ biological rhythms. This approach not only enhances drug efficacy and safety but also contributes to the broader goal of personalized medicine, offering more targeted and effective healthcare solutions. In conclusion, the field of chronopharmacokinetics underscores the importance of timing in drug administration. As research in this area continues to evolve, it holds the promise of improving therapeutic outcomes across various medical disciplines, paving the way for more effective and personalized treatments.

Acknowledgments

The corresponding author would like to thank to Miss Michelle Guadarrama, for providing required support in the translation of the manuscript.

Conflict of interest

The author(s) declares no conflict of interest

Funding sources

The author(s) received no financial support for the research, authorship, and/or publication of this article

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