6 J Rational Pharmacother Res Vol. 1 No.

1,January - March 2013

J Rational Pharmacother Res
An Official Publication of ISRPT
REVIEW ARTICLE
From the Department of Pharmacology, Govt Medical College & * Superspeciality Hospital Jammu, J&K - India
Correspondence to : Dr Brij Mohan Gupta, Associate Professor, Deptt. of Pharmacology, Govt Medical College Jammu, J&K- India
E mail: drbrijmohangupta18@yahoo.com
Chronopharmacology: An Overview
Rohini Gupta, Brij Mohan Gupta, Vijay Khajuria, Nusart Kreem Bhat, Apeksha Gupta*
Variation in the behavior has always attracted the
Research workers. In 1729, French astronomer Jean
Jacques d'Ortous de Mairan began his research on
biological rhythm by observing changes in plants in relation
to day and night. Pittendrigh in 1967 proposed that animals
have an internal time keeping device, a circadian clock.
Thus, emerging concepts "chronobiology - science of
biological rhythms and biological time structure" and
"circadian rhythm - oscillations in the biological,
physiological and behavioural function of an organism
with a periodicity of 24 hours" were incorporated in the
medical terminology.
In early 1970s, 'chronopharmacology' became
recognized as a scientific domain of investigation to
understand the periodic and predicable changes in both,
desired effects and tolerance of medication. It is defined
as a science dealing with the optimization of drug effects
and the minimization of adverse effects by timing
medications in relation to the biological rhythm.
[1]
The
rhythms that derive from the internal timing system and
persist in the absence of environmental stimuli are called
circadian from the Latin words circa (approximately) and
dies (day). The circadian clock imposes a rhythm on many
metabolic pathways and may influence drug metabolism
in a variety of ways. Circadian variation in the activity of
many gastrointestinal, hepatic and renal processes could
explain why the absorption, distribution, metabolism and
excretion of drugs change as a function of the time of
drug administration. Chronopharmacology utilizes rhythms
of physiology to try to synchronize concentration and
dosing of medications to increase their efficacy and safety.
The clinical use of chronopharmacology in regulating both
pharmacodynamics and pharmacokinetics is increasingly
appreciated by the medical fraternity.
[2]
Drug Absorption Distribution, Metabolism and
Excretion
The absorption of a number of widely used drugs such
as nitrates, benzodiazepines, calcium channel blockers,
acetaminophen and antidepressants is found to be more
rapid after oral administration in the morning compared
to in the evening.
[3-8]
The rate of absorption is increased,
the maximal plasma serum concentration is greater and
Abstract
The circadian clock imposes a rhythm on many metabolic pathways and may influence drug metabolism in
a variety of ways. Circadian variation in the activity of many gastrointestinal, hepatic and renal processes
could explain why the absorption, distribution, metabolism and excretion of drugs change as a function of
the time of drug administration. Chronopharmacology utilizes rhythms of physiology to try to synchronize
concentration and dosing of medications to increase their efficacy and safety.
Key Words
Chronopharmacology, Biological Clock, Circadian Rhythm
Received- 26.1.13 Revised -30.1.13 Accepted-12.2.13
Introduction
Vol. 1 No. 1, January - March 2013 J Rational Pharmacother Res 7
J Rational Pharmacother Res
An Official Publication of ISRPT
the time after administration needed to obtain maximal
plasma levels is shorter when the drugs are taken at the
beginning of the day. This difference in drug absorption
at different times of the day is a result of diurnal changes
in various aspects of physiology. Drug solubility and route
of administration may influence the diurnal variability of
drug absorption. Lipid-soluble drugs are more likely to
show temporal variations in pharmacokinetics than do
water-soluble drugs.
[2]
Time-dependent variation in drug binding to plasma
proteins influences the distribution of drugs that are highly
protein bound and have a small volume of distribution.
The binding capacity of the plasma corticosteroid-binding
globulin, transcortin, for prednisolone varies with time in
humans, with maximum binding occurring at midnight and
minimum at 8.00 o'clock in the morning. Drug distribution
is also dependent on the permeability of membranes to
drugs.
[2,9]
The liver is a major site of drug metabolism and
oxidation and conjugation to endogenous substrates are
the two main reactions in drug metabolism which change
with time. The cytochrome P450 monoxygenase system
is the main system responsible for drug oxidation. Protein
levels of cytochrome P450 enzymes also describe
circadian rhythms.
[2]
Diurnal rhythms have been described for glomerular
filtration rate, effective renal plasma flow, tubular
secretion, urine output and urinary excretion of electrolytes
and many endogenous substances.
[10]
These rhythms may
result in different excretion rates for drugs at different
times of the day. Diurnal variations in systemic blood
pressure, the renin-angiotensin system and renal blood
flow are responsible for time-dependent changes in renal
hemodynamics.
[2]
Molecular Basis of Circadian Clock
The circadian system is organized in a hierarchical
manner with a master clock located at the
suprachiasmatic nucleus (SCN), which lies above the
optic chiasm at the base of the hypothalamus. The SCN
receives information about the day-night cycle through
photic input via a direct retinal innervation, the
retinohypothalamic tract.
[11]
Neuropeptidergic signaling
is responsible for interneuronal synchronization within the
SCN.
[12]
A second synchronizer of the SCN clockwork
is melatonin, a hormone secreted by the pineal gland.
[13,14]
The master oscillator located at the SCN communicates
day-night cycle phase information to the rest of the body.
Through neuronal and humoral signals, the SCN sends
this information to peripheral circadian clocks that exist
in almost all cells of the body and synchronize them to
the same phase.
[15]
The identification of the circadian clock at the molecular
level makes possible the transition from observational
studies of drug efficacy and toxicity at different times of
the day to cause-effect studies that provide a link between
the circadian clock and drug metabolism. When the
circadian clock is disturbed, there is a change in drug
effectiveness or toxicity.
[2]
Timing of Drug Admnistration
Many chronic and acute medical conditions exhibit
prominent circadian patterns of symptom manifestation
and severity. Among them, cardiovascular events, such
as angina pectoris, ventricular arrhythmia, acute
myocardial infarction, sudden cardiac death and
thrombotic and hemorrhagic stroke, show strikingly higher
frequency of appearance in the morning.
[2,16-20]
The
clinical severity of allergic rhinitis and bronchial asthma
is most pronounced in early morning hours and timed
administration of medications against them as been
associated with sleep disturbances and melatonin has been
suggested as a potential treatment.
[21]
However, comparative evaluations of
chronopharmacological strategies have been few - in
blood pressure and some forms of cancer - and even
then only with evaluation of impact on surrogate variables
rather than clinical outcomes.
[2]
The controlled-onset, extended-release calcium channel
blocker verapamil was the first special drug-delivery
medication specifically designed for the therapy of
hypertension. The drug-delivery technology of this tablet
delays the release of verapamil for ~4-5 hours following
its recommended bedtime ingestion. Medication is released
thereafter so the highest blood concentration is achieved
in the morning around the time of awakening, with an
elevated level sustained throughout diurnal activity.
[22]
Bedtime administration has proven to be more effective
not only for calcium channel blockers but also for a
number of other antihypertensive drugs such as
angiotensin-converting enzyme inhibitors, alpha-
adrenergic receptor antagonists and angiotensin II
8 J Rational Pharmacother Res Vol. 1 No.1,January - March 2013
J Rational Pharmacother Res
An Official Publication of ISRPT
receptor blockers
.[23,24,25]
Circadian timing of drug delivery can play a significant
role in anticancer therapeutic effectiveness and
tolerability.
[2]
The misalignment of circadian rhythms in
physiology, endocrinology, metabolism and behavioural
rhythms with the external environment is common among
humans those work in night shifts or routinely travel
across time zones. An increased incidence of breast
cancer has been observed among female flight
attendants.
[26,27]
Also, increased risk of breast, colon,
prostate and endometrial cancers has been associated
with rotating or permanent night shift work.
[28,29,30]
The
relationship between the rest-activity cycle and cancer
prognosis in humans has been investigated in patients
with metastatic colorectal cancer. Patients with marked
activity rhythms show a more favourable tumor response
and survival rate and report a better quality of life
.[31]
Clinical studies for treatment of ovarian, renal, breast
and liver cancers showed that controlling circadian timing
of dosage often leads to decrease in drug toxicity.
[32,33,34]
When 5-fluorouracil (5-FU) is delivered at the same rate
over the course of the day by continuous intravenous
infusion, the mean plasma 5-FU levels fluctuate, with the
highest levels late at night and lowest levels at
midday.
[35,36]
The pharmacokinetics of 5-FU suggests that
a chronomodulated delivery schedule would be most
effective for cancer treatment, and numerous clinical trials
have highlighted the benefits of chronotherapy of 5-FU,
particularly in the treatment of colon cancer.
[37]
Toxicity
and efficacy of the platinum-based anticancer drugs
cisplatin and oxaliplatin fluctuate with a diurnal rhythm,
pointing towards a possible mechanism for these
chronomodulated effects. Dosing of oxaliplatin during
early to mid-night led to decreased toxicity and tumor
growth as well as an increase in life span.
[2]
Future Approach
Now a day's pulsatile drug delivery is gaining popularity.
The prime advantage in this drug delivery is that drug is
released when necessity comes. As a result chance of
development of drug resistance seen in conventional and
sustained release formulations can be reduced.
Furthermore, some anticancer drugs are very toxic and
these drugs give hazardous problems in conventional and
sustained release therapies. Pulsatile therapy is mainly
applicable where sustained action is not required and drugs
are toxic. Key point of development of this formulation is
to find out circadian rhythm which will control the release
of drug from the device. Another point is absence of
suitable rhythmic biomaterial which should be
biodegradable, biocompatible and reversibly responsive
to specific biomarkers in rhythmic manner. Regulatory is
another big question. Many research trials are going on
the pulsatile drug delivery to discover circadian rhythm
with suitable device in the world. In future this delivery
will be a leading way to deliver therapeutic agents due to
its some unique characters like low chance of dose
dumping, patient compliance and the above factors.
[38]
Recently developed Spheroidal Oral Drug Absorption
System (SODAS) technology is based on the production
of controlled release beads and it is characterized by its
inherent flexibility, enabling the production of customized
dosage forms that respond directly to individual drug
candidate needs. Chronotherapeutics Oral Drug
Absorption System (CODAS) is a multiparticulate system
which is designed for bedtime drug dosing, incorporating
a 4-5 hours delay in drug delivery. The TIMERx
Technology combines primarily Xanthan and Locust bean
gums mixed with dextrose. The physical interaction
between these components works to form a strong binding
gel in the presence of water.
[39]
Conclusion
Circadian rhythm of the body is an important concept
for understanding the optimum need of drug in the body.
There is a constant need for new delivery systems that
can provide increased therapeutic benefits to the patients.
Pulsatile drug delivery is one such system that, by
delivering drug at the right time, right place and in right
amounts, holds good promises of benefit to the patients
suffering from chronic problems. Thus designing of
proper pulsatile drug delivery will enhances the patient
compliance, optimum drug delivery to the target site and
minimizes the undesired effects.
1. Motghare VM, Faruqui AA, Dudhgaonkar S, Turankar AV.
Chronopharmacology. In: Seth SD, Seth V(edt) Text Book
of Pharmacology, 3
rd
edition, Chapter 105, 2009.pp.
xvi7-8.
2. Paschos GK, Baggs JE, Hogenesch JB, FitzGerald GA.
The role of clock genes in pharmacology. In: Cho AK,
Blaschke TF, Insel PA, Loh HH (editors), Annual Review
of Pharmacology and Toxicology. Palo Alto, California, USA
2010; vol. 50 : pp. 187-214.
3. Scheidel B, Lemmer B. Chronopharmacology of oral nitrates
in healthy subjects. Chronobiol Inst 1991; 8: 409-19.
4. Nakano S, Watanabe H, Nagai K, Ogawa N. Circadian stage-
dependent changes in diazepam kinetics. Clin Pharmacol
Ther 1984; 36: 271-77.
References
Vol. 1 No. 1, January - March 2013 J Rational Pharmacother Res 9
J Rational Pharmacother Res
An Official Publication of ISRPT
5. Muller FO, Van Dyk M, Hundt HK, Joubert AL, Luus
HG, et al. Pharmacokinetics of temazepam after day-time
and night-time oral administration. Eur J Clin Pharmacol
1987; 33: 211-14.
6. Lemmer B, Nold G, Behne S, Kaiser R.
Chronopharmacokinetics and cardiovascular effects of
nifedipine. Chronobiol Int 1991; 8: 485-94.
7. Kamali F, Fry JR, Bell GD. Temporal variations in
paracetamol absorption and metabolism in man. Xenobiotica
1987; 17: 635-41.
8. Nakano S, Hollister LE. Chronopharmacology of
amitripryline. Clin Pharmacol 1983; 33: 453-59.
9. Angeli A, Frajria R, De Paoli R, Fonzo D, Ceresa F. Diurnal
variation of prednisolone binding to serum corticosteroid-
binding globulin in man. Clin Pharmacol Ther 1978; 23:
47-53.
10. Levi F, Schibler U. Circadian rhythms: mechanism and
therapeutic implication. Ann Rev Pharmacol Toxicol 2007;
47: 593-628.
11. Hastings MH, Herzog ED. Clock genes, oscillators and
cellular networks in the suprachiasmatic nuclei. J Biol
Rhythms 2004; 19: 400-13.
12. Maywood ES, Reddy AB, Wong GK, O'Neill JS, O'Brien
JA, et al. Synchronization and maintenance of timekeeping
in suprachiasmatic circadian clock cells by neuropeptidergic
signaling. Curr Biol 2006; 16: 599-605.
13. Cassone VM, Chesworth MJ, Armstrong SM. Entrainment
of rat circadian rhythms by daily injection of melatonin
depends upon the hypothalamic suprachiasmatic nuclei.
Physiol Behav 1986; 36: 1111-21.
14. Johnson RF, Moore RY, Morin LP. Loss of entrainment
and anatomical plasticity after lesions of the hamster
retinohypothalamic tract. Brain Res 1988; 460: 297-313.
15. Schibler U, Sassone-Corsi P. A web of circadian pacemakers.
Cell 2002; 111: 919-22.
16. Rocco MB, Barry J, Campbell S, Nabel E, Cook EF.
Circadian variation of transient myocardial ischemia in
patients with coronary artery disease. Circulation 1987;
75: 395-400.
17. Venditti FJ Jr, John Rm, Hull M, Tofler GH, Shahian DM,
Martin DT. Circadian variation in defibrillation energy
requirements. Circulation 1996; 94: 1607-12.
18. Cohen MC, Rohtla KM, Lavery CE, Muller JE, Mittleman
MA. Meta-analysis of the morning excess of acute
myocardial infarction and sudden cardiac death. Am J Cardiol
1997; 79: 1512-16.
19. Elliott WJ. Circadian variation in the timing of stroke onset:
a meta-analysis. Stroke 1998; 29: 992-96.
20. Smolensky MH, Lemmer B, Reinberg AE. Chronobiology
and chemotherapy of allergic rhinitis and bronchial asthma.
Adv Drug Deliv Rev 2007; 59: 852-82.
21. White WB, Anders RJ, MackIntyre JM, Black HR, Sica
DA. Nocturnal dosing of a novel delivery system of
verapamil for systemic hypertension. Verapamil Study
Group. Am J Cardiol 1995; 76: 375-80.
22. Morgan T, Anderson A, Jones E. The effect of 24-h blood
pressure control of an angiotensin converting enzyme
inhibitor (perindopril) administered in the morning or at
night. J Hypertens 1997; 15: 205-11.
23. Panza JA, Epstein SE, Quyyami AA. Circadian variation
in vascular tone and its relation to alpha-symphathetic
vasoconstrictor activity. N Engl J Med 1991; 325: 986-90.
24. Hermida RC, Calvo C, Ayala DE, Dominguez MJ, Covelo
M. Administration time-dependent effects of valsartan on
ambulatory blood pressure in hypertensive subjects.
Hypertension 2003; 42: 283-90.
25. Rafnsson V, Tulinius H, Jonasson JG, Hrafnkelsson J. Risk
of breast cancer in female flight attendants: a population-
based study (Iceland). Cancer Causes Control 2001; 12:
95-101.
26. Erren TC, Pape HG, Reiter RJ, Piekarski C.
Chronodisruption and cancer. Naturwissenschaften 2008;
93: 367-82.
27. Davis S, Mirick DK, Stevens RD. Night shift work, light at
night and risk of breast cancer. J Natl Cancer Inst 2001; 93:
1557-62.
28. Schernhammer ES, Kroenke CH, Laden F, Hankison SE.
Night work and risk of breast cancer. Epidimiology 2006;
17: 108-11.
29. Viswanathan AN, Handkinson SE, Schernhammer ES. Night
shift work and the risk of endomerial cancer. Cancer Res
2007; 67: 10618-22.
30. Mormont MC, Waterhouse J, Bleuzen P, Giacchetti S, Jami
A. Marked 24-hr rest/activity rhythms are associated with
better quality of life, better, response and longer survival in
patients with metastatic colorectal cancer and good
performance status. Clin Cancer Res 2000; 6: 3038-45.
31. Rivard GE, Infante-Rivard C, Hoyous C, Champagne J.
Maintenance chemotherapy for childhood acute
lymphoblastic leukaemia: better in the evening. Lancet 1985;
2: 1264-66.
32. Depres-Brummer P, Berthault-Cvitkovic F, Levi F, Brienza
S, Vannetzel JM, et al. Circadian rhythm-modulated (CRM)
chemotherapy of metastatic breast cancer with
mitoxantrone, 5-fluorouracil and folic acid: preliminary
results of a phase I trial. J Infus Chemother 1995; 5: 144-7.
33. Hrushesky WJ. Circadian timing of cancer chemotherapy.
Science 1985; 228: 73-5.
34. Bressolle F, Joulia JM, Pinguet F, Ychou M, Astre C.
Circadian rhythm of 5-fluorouracil population
pharmacokinetics in patients with metastatic colorectal
cancer. Cancer Chemother Pharmacol 1999; 44: 295-302.
35. Takimoto CH, Yee LK, Venzon DJ, Schuler B, Grollman F
.High inter- and intrapatient variation in 5-fluorouracil
plasma concentrations during a prolonged drug infusion.
Clin Cancer Res 1999; 5: 1347-52.
36. Mormont MC, Levi F. Cancer chronotherapy: principles,
applications and perspectives, Cancer 2003; 97: 155-69.
37. Granda TG, D'Attino RM, Filipski E, Vrignaud P, Garufi
C, et al. Circadian optimisation of irinotecan and oxaliplatin
efficacy in mice with Glasgow osteosarcoma, Br J Cancer
2002; 86: 999-1005.
38. Rajput M, Sharma R, Kumar S, Jamil F, Sissodia N, Sharma
S. Pulsatile drug delivery system: a review. Int J Res Pharma
Biomed Sci 2012: 3: 118-24.
39. Maurya KK, Semwal BC, Singh N, Srivastava V, Ruqsana
K. Chronopharmacology: a tool for therapy of diseases.
Inter Res J Pharm 2012; 3: 128-32.
Source of Support Nil Conflict of Interest Declared
How to Cite This Article
Gupta R , Gupta BM, Khajuria V, Bhat NK, Gupta A. Chronopharmacology: An Overview. J Rational Pharmacother
Res 2013; 1(1):6-9