This document discusses chronopharmacokinetics, which investigates how drug plasma levels vary over the course of a day due to biological rhythms. It examines how factors like absorption, distribution, metabolism, and excretion of drugs are influenced by circadian rhythms in processes like gastric emptying, liver enzyme activity, and kidney function. Understanding how these rhythms impact drug kinetics can help optimize dosing for safety and efficacy by administering drugs at times when concentrations are least toxic or most therapeutic.

2. • DEFINITION
• INTRODUCTION
• AIM
• BODY RHYTHMS
• CIRCADIAN RHYTHMS
• CLASSIFICATION
• FACTORS EFFECTING CIRCADIAN RHYTHMS
• DRUGS THAT UNDERGO CHRONOKINETICS
• CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
• LIMITATIONS
• APPLICATIONS
• CONCLUSION

3. • Chronopharmacokinetics investigates the variation in drug
plasma levels as a function of time of day and the mechanisms
responsible for time dependent variations.
• It deals with the study of the temporal changes in absorption,
distribution, metabolism and elimination.

4. • Drug Absorption, Distribution, Metabolism and Elimination
are influenced by many different physiological functions
of the body which may vary with time.
• Hence the time of the day has to be regarded as an
additional variable influencing the kinetics of a drug.
• The time of administration is a possible factor of variation
in the kinetics of a drug.

5. • The main aim is to know the moment of administration of
drug to achieve desired drug plasma concentration so as to
eliminate chances of discomfort felt by the patient due to the
higher intensity of symptoms of a disease for which drug
therapy is required.
• These studies also aim to administer drugs at an optimum
time so that the resulting drug plasma concentrations are
either or least toxic or totally safe for body.

6. • These are the biological process that show cyclic
variations over time.
• Types of body rhythms:
 Circadian Rhythms :which lasts for about one day.
Ex : Sleep walking, body temperature.
 Ultradian Rhythms: which lasts for shorter than a day, like
seconds. Ex: heartbeat
 Infradian Rhythms :which lasts for longer than a day, like
monthly rhythms- menstrual cycle

7. Sleep cycle

8. Sleep cycle
• brain

10. • It is altered by circadian changes in
gastric emptying time
gastrointestinal blood flow
gastric acid secretion and pH
• Most lipophilic drugs seem to be absorbed faster when the
drug is taken in the morning compared with the evening.
Ex: absorption in valproic acid larger in the morning than in
the evening.

11. • It is altered by circadian changes in
body size and composition
blood flow to various organs
drug protein binding
Peak plasma concentration of plasma proteins like
albumin occurs early in the afternoon, while troughs are found
during .
Ex: Maximum binding of neoplastics like cisplastin to
plasma proteins is in the afternoon and minimum in the
morning.

12. • It is altered by circadian changes in liver enzyme activity,
hepatic blood flow.
• For drugs with low extraction ratio depends on liver enzyme
activity.
• For drugs with extraction ratio depends on hepatic blood flow.

13. • It is altered by circadian changes in
Glomerular filtration
Renal blood flow
Urinary pH
Tubular reabsorption
• All lower during the resting period than in activity period
Ex: acidic drugs like sodium salicylate excreted quickly
after evening than morning administration.

15.  CIRCARDIAN CHANGES IN DRUG ABSORPTION
It is altered due to changes in
• Gastric acid secretion
• pH
• Motility
• Gastric emptying time-longer for evening meal - Tmax
• Gl blood flow
• Routes of administration
• Absorption is also altered due to physicochemical properties-
lipophilicity or hydrophilicity.
• Ex:
Most lipophilic drugs like phenytoin seems to be absorbed faster
when the drug is taken in morning compared with the evening.

16. • Distribution is altered due to circadian changes in:
• Body size and composition
• Blood flow to organs
• Plasma protein binding
• Membrane permeability to drugs
Peak plasma concentration of plasma proteins like albumin
and 1- glycoprotein are time dependent and occurs early in the
afternoon when compared during the night.
Ex:
Drug concentration of free fraction of phenytoin and
valproic acid have been found to vary in 24 hrs scale.

17. Metabolism is altered due to circadian changes in
• Liver
• Cytochrome P-450 monooxygenase ex: beta hydrocortisol
• Hepatic blood flow
• First pass elimination of drugs
• Enzyme activity
• Temporal variation in oxidase activity of the liver and
concentration of microsomal enzyme at the beginning of
activity.
• Temporal variations in conjugation i.e., hepatic
glucuronidation and sulfation. Ex: paracetamol

18. • Systemic clearance decreases at night and increases during day
time.
• For drugs with low extraction ratios fluctuations in intrinsic
metabolic clearance in plasma protein binding.
• Ex: valproic acid, clonazepam.
Excretion is altered due to circadian changes in:
• Glomerular filtration
• Renal blood flow
• Urinary pH
• Tubular reabsorption
• Urine output
• Urinary excretion of electrolytes.
All these are lowered during the resting period than in activity
period.

19. • The drug concentration will be maximum during the dark
period (2:00 A.M-5:00 A.M)
• It will be minimum during the light period (14:00 PM-17:00
PM)

20. Induction of enzymes by the drug is responsible for elimination
there by increase the clearance of the drug.
Ex: Repeated doses of carbamazepine ,rifampicin induces the
enzymes reponsible for their elimination.
The metabolites formed increase in concentration and further
inhibit metabolism of the parent drug.
Ex: xanthine oxidase inhibitor-allopurinal,verapamil.

21. • Food
• Meal timing
• GI pH
• Intestinal motility
• Digestive secretions
• Intestinal blood flow
• Light
• The timing of exposure to light
• The length of exposure to light
• Intensity and wavelength of light

22. • Antibiotics-aminoglycosides
• Anti hypertensive drugs-propranolol,nifidipine
• Anti epileptic drugs-valproic acid
• Anti cancer drug-cyclosporine,methotrexate
• NSAIDS –Ketoprofen,indomethacin

23. • Enteric coatings
• Layered systems
• Time controlled explosion systems (TES)
• Sigmoidal release systems (SRS)
• Press coated systems

25. • Difference between species-rodents and humans
• Harmful to rodents/experimental animal
• Large number of animals
• Very complex anti-cancer drug development

26. • ASTHMA
Ex: Theophylline
• GASTRO INTESTINAL DISEASES
Ex: Ranitidine
• ARTHRITIS
Ex: Ibuprofen
• CARDIO VASULAR DISEASES
• CANCER

27. • The concept of drug treatment was earlier “right drug for the
right person’’ is now changed to “right dose for the right
person at right time”.
• Time dependent pharmacokinetics can sometimes be
responsible for daily variation drug effects or adverse effects.
• Hence time of the day should be considered as an additional
variable that influences the kinetics of the drug.