Authors
Department of Toxicology, Hacettepe University, Ankara, Turkey
Abstract
For many decades, researchers are aware of the importance of circadian rhythm in
physiological/biochemical properties and drug metabolism. Chronopharmacology is the study
of how the effects of drugs vary with biological timing and endogenous periodicities. It has
been attaching substantial attention in the last years. Chronopharmacodynamics mainly deals
with the biochemical and physiological effects of drugs on the body, the mechanisms of drug
action, the relationship between drug concentration and effect in relation to circadian clock.
In this review, we will focus on mammalian circadian pharmacodynamics and discuss new
chronotherapy approaches. Moreover, we will try to highlight the chronopharmacodynamics
of cardiovascular drugs, anti‑cancer drugs, analgesics and non‑steroidal anti‑inflammatory
drugs (NSAIDs) and give some practical concerns for clinical pharmacists and pharmacy
practitioners, concerning this issue.
Keywords
- Reppert SM, Weaver DR. Molecular analysis of mammalian
circadian rhythms. Annu Rev Physiol 2001;63:647‑76.
2. Toh KL. Basic science review on circadian rhythm biology
and circadian sleep disorders. Ann Acad Med Singapore
2008;37:662‑8.
3. Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown
GM, Pandi‑Perumal SR. Melatonin: A pleiotropic, orchestrating
regulator molecule. Prog Neurobiol 2011;93:350‑84.
4. Hut RA, Beersma DG. Evolution of time‑keeping mechanisms:
Early emergence and adaptation to photoperiod. Philos Trans
R Soc Lond B Biol Sci 2011;366:2141‑54.
5. Kalsbeek A, Scheer FA, Perreau‑Lenz S, La Fleur SE, Yi CX,
Fliers E, et al. Circadian disruption and SCN control of energy
metabolism. FEBS Lett 2011;585:1412‑26.
6. Hut RA, van der Zee EA. The cholinergic system,
circadian rhythmicity, and time memory. Behav Brain Res
2011;221:466‑80.
7. Froy O. The circadian clock and metabolism. Clin Sci (Lond)
2011;120:65‑72.
8. Lévi F. The circadian timing system, a coordinator of
life processes. Implications for the rhythmic delivery of
cancer therapeutics. Conf Proc IEEE Eng Med Biol Soc
2006;(Suppl):6736‑9.
9. Gachon F, Nagoshi E, Brown SA, Ripperger J, Schibler U. The
mammalian circadian timing system: From gene expression
to physiology. Chromosoma 2004;113:103‑12.
10. Maury E, Ramsey KM, Bass J. Circadian rhythms and
metabolic syndrome: From experimental genetics to human
disease. Circ Res 2010;106:447‑62.
11. Kalsbeek A, Yi CX, Cailotto C, la Fleur SE, Fliers E, Buijs
RM. Mammalian clock output mechanisms. Essays Biochem
2011;49:137‑51.
12. Mazzoccoli G. The timing clockwork of life. J Biol Regul
Homeost Agents 2011;25:137‑43.
13. Bass J, Takahashi JS. Circadian integration of metabolism and
energetics. Science 2010;330:1349‑54.
14. Gachon F, Firsov D. The role of circadian timing system on
drug metabolism and detoxification. Expert Opin Drug Metab
Toxicol 2011;7:147‑58.
15. Lees P.Cunningham FM, Elliott J. Principles of
pharmacodynamics and their applications in veterinary
pharmacology. J Vet Pharmacol Ther 2004;27:397‑414.
16. Ohdo S. Chronopharmacology focused on biological clock.
Drug Metab Pharmacokinet 2007;22:3‑14.
17. Reinberg AE. Concepts in chronopharmacology. Annu Rev
Pharmacol Toxicol 1992;32:51‑66.
18. Ohdo S. Changes in toxicity and effectiveness with timing of
drug administration: Implications for drug safety. Drug Saf
2003;26:999‑1010.
19. Smolensky MH, Peppas NA. Chronobiology, Drug delivery
and chronotherapeutics. Adv Drug Deliv Rev 2007;59:828‑51.
20. Ohdo S, Koyanagi S, Matsunaga N. Chronopharmacological
strategies: Intra‑ and inter‑individual variability of molecular
clock. Adv Drug Deliv Rev 2010;62:885‑97.
21. Takane H, Ohdo S, Yamada T, Yukawa E, Higuchi S.
Chronopharmacology of antitumor effect induced by
interferon‑beta in tumor‑bearing mice. J Pharmacol Exp Ther
2000;294:746‑52.
22. Ohdo S, Wang DS, Koyanagi S, Takane H, Inoue K, Aramaki H,
et al. Basis for dosing time‑dependent changes in the antiviral
activity of interferon‑alpha in mice. J Pharmacol Exp Ther
2000;294:488‑93.
23. Danel T, Touitou Y. Chronobiology of alcohol: From
chronokinetics to alcohol‑related alterations of the circadian
system. Chronobiol Int 2004;21:923‑35. - 24. Huang W, Ramsey KM, Marcheva B, Bass J. Circadian rhythms,
sleep, and metabolism. J Clin Invest 2011;121:2133‑41.
25. Hogenesch JB, Herzog ED. Intracellular and intercellular
processes determine robustness of the circadian clock. FEBS
Lett 2011;585:1427‑34.
26. Hermida RC, Ayala DE, Fernández JR, Portaluppi F, Fabbian
F, Smolensky MH. Circadian rhythms in blood pressure
regulation and optimization of hypertension treatment
with ACE inhibitor and ARB medications. Am J Hypertens
2011;24:383‑91.
27. Potts AL, Cheeseman JF, Warman GR. Circadian rhythms
and their development in children: Implications for
pharmacokinetics and pharmacodynamics in anesthesia.
Paediatr Anaesth 2011;21:238‑46.
28. Ohdo S, Koyanagi S, Matsunaga N, Hamdan A. Molecular
basis of chronopharmaceutics. J Pharm Sci 2011;100:3560‑76.
29. Bode‑Böger SM, Kojda G. Organic nitrates in cardiovascular
disease. Cell Mol Biol (Noisy‑le‑grand) 2005;51:307‑20.
30. Aschoff J. Desynchronization and resynchronization of human
circadian rhythms. Aerosp Med 1969;40:844‑9.
31. Stanton AV. Calcium channel blockers. The jury is still
out on whether they cause heart attacks and suicide. BMJ
1998;316:1471‑3.
32. White WB, LaRocca GM. Chronopharmacology of
cardiovascular therapy. Blood Press Monit 2002;7:199‑207.
33. Bakris G, Sica D, Ram V, Fagan T, Vaitkus PT, Anders RJ.
A comparative trial of controlled‑onset, extended‑release
verapamil, enalapril, and losartan on blood pressure and heart
rate changes. Am J Hypertens 2002;15:53‑7.
34. Hrushesky W, Wood P, Levi F, von Roemeling R, Bjarnason
G, Focan C, et al. A recent illustration of some essentials
of circadian chronotherapy study design. J Clin Oncol
2004;22:2971‑2.
35. Lévi F, Okyar A, Dulong S, Innominato PF, Clairambault J.
Circadian timing in cancer treatments. Annu Rev Pharmacol
Toxicol 2010;50:377‑421.
36. Stupp R, Weber DC. The role of radio‑and chemotherapy in
glioblastoma. Onkologie 2005;28:315‑7.
37. Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites
MC, et al. Phase III, double‑blind, randomized study
comparing lapatinib plus paclitaxel with placebo plus
paclitaxel as first‑line treatment for metastatic breast cancer.
J Clin Oncol 2008;26:5544‑52.
38. Motzer RJ, Basch E. Targeted drugs for metastatic renal cell
carcinoma. Lancet 2007;370:2071‑3.
39. Shepherd FA. A targeted approach to reducing lung cancer
mortality. J Clin Oncol 2005;23:3173‑4.
40. Mok TS, Ramalingam SS. Maintenance therapy in
nonsmall‑cell lung cancer: A new treatment paradigm. Cancer
2009;115:5143‑4.
41. Innominato PF, Lévi FA, Bjarnason GA. Chronotherapy and
the molecular clock: Clinical implications in oncology. Adv
Drug Deliv Rev 2010;62:979‑1001.
42. Hrushesky W, Wood P, Levi F, von Roemeling R, Bjarnason
G, Focan C, et al. A recent illustration of some essentials
of circadian chronotherapy study design. J ClinOncol
2004;22:2971‑2.
43. Garufi C, Ettorre GM, Vanni B, Torsello A, Terzoli E.
Neoadjuvant chemotherapy for metastatic colon cancer: Too
much caution and still too much to be assessed. J Clin Oncol
2006;24:2217‑8.
44. Longley DB, Harkin DP, Johnston PG. 5‑fluorouracil:
Mechanisms of action and clinical strategies. Nat Rev Cancer
2003;3:330‑8.
45. Bjarnason GA, Jordan R. Rhythms in human gastrointestinal
mucosa and skin. Chronobiol Int 2002;19:129‑40.
46. Wood PA, Du‑Quiton J, You S, Hrushesky WJ. Circadian
clock coordinates cancer cell cycle progression, thymidylate
synthase, and 5‑fluorouracil therapeutic index. Mol Cancer
Ther 2006;5:2023‑33.
47. Smaaland R, Sothern RB, Laerum OD, Abrahamsen JF.
Rhythms in human bone marrow and blood cells. Chronobiol
Int 2002;19:101‑27.
48. Lincoln DW 2nd, Hrushesky WJ, Wood PA. Circadian
organization of thymidylate synthase activity in normal
tissues: A possible basis for 5‑fluorouracil chronotherapeutic
advantage. Int J Cancer 2000;88:479‑85.
49. Bjarnason GA, Jordan RC, Wood PA, Li Q, Lincoln DW,
Sothern RB, et al. Circadian expression of clock genes in human
oral mucosa and skin: Association with specific cell‑cycle
phases. Am J Pathol 2001;158:1793‑801.
50. Etienne‑Grimaldi MC, Cardot JM, François E, Renée N,
Douillard JY, Gamelin E, et al. Chronopharmacokinetics of oral
tegafur and uracil in olorectal cancer patients. Clin Pharmacol
Ther 2008;83:413‑5.
51. Ohdo S, Wang DS, Koyanagi S, Takane H, Inoue K, Aramaki
H, et al. Basis for dosing time‑dependent changes in the
antiviral activity of interferon‑α in mice. J Pharmacol Exp
Ther 2000;294:488‑93.
52. Nakagawa H, Takiguchi T, Nakamura M, Furuyama A,
Koyanagi S, Aramaki H, et al. Basis for dosing time‑dependent
change in the anti‑tumor effect of imatinib in mice. Biochem
Pharmacol 2006;72:1237‑45.
53. Mahdi AA, Fatima G, Das SK, Verma NS. Abnormality of
circadian rhythm of serum melatonin and other biochemical
parameters in fibromyalgia syndrome. Indian J Biochem
Biophys 2011;48:82‑7.
54. Ray M, Mediratta PK, Mahajan P, Sharma KK. Evaluation of
the role of melatonin in formalin‑induced pain response in
mice. Indian J Med Sci 2004;58:122‑30.
55. Labrecque G, Vanier MC. Biological rhythms in pain
and in the effects of opioid analgesics. Pharmacol Ther
1995;68:129‑47.
56. Gallerani M, Manfredini R, Dal Monte D, Calò G, Brunaldi V,
Simonato M. Circadian differences in the individual sensitivity
to opiate overdose. Crit Care Med 2001;29:96‑101.
57. Martín del Campo AF, Dowson JH, Herbert J, Paykel ES.
Diurnal variations in endocrine and psychological responses
to 0.2mg/kg naloxone administration in patients with major
depressive disorder and matched controls. J Affect Disord
2000;57:37‑47.
58. Yoshida M, Ohdo S, Takane H, Tomiyoshi Y, Matsuo A,
Yukawa E, et al. Chronopharmacology of analgesic effect and
its tolerance induced by morphine in mice. J Pharmacol Exp
Ther 2003;305:1200‑5.
59. Li G, Rhodes JS, Girard I, Gammie SC, Garland T Jr.
Opioid‑mediated pain sensitivity in mice bred for high
voluntary wheel running. Physiol Behav 2004;83:515‑24.
60. Boom M, Grefkens J, van Dorp E, Olofsen E, Lourenssen G,
Aarts L, et al. Opioid chronopharmacology: Influence of timing
of infusion on fentanyl’s analgesic efficacy in healthy human
volunteers. J Pain Res 2010;21:183‑90. - 61. Hummel T, Kraetsch HG, Lötsch J, Hepper M, Liefhold J, Kobal
G. Analgesic effects of dihydrocodeine and tramadol when
administered either in the morning or evening. Chronobiol
Int 1995;12:62‑72.
62. Cui Y, Sugimoto K, Araki N, Fujimura A. Evaluation
of chronopharmacodynamics of indomethacin by the
kaolin‑induced pain model in mice. Chronobiol Int
2003;20:473‑84.
63. Baydar T, Erkekoglu P. Circadian rhtyhm changes in elderly.
In: Kutsal YG, editor. Hacettepe University Geriatric Science
Research Center. (GEBAM). Ankara: Turkish Pharmacists
Association Press; 2009. p. 97‑8.
64. Baydar T, Erkekoglu P. Circadian rhthyhm vegeriatrics.
Research and Application Center of geriatric Sciences Bulletin
2009;1:1.
)