BY
SAHITHI GADDE
(Y13MPPC140003)
DEPARTMENT OF
PHARMACEUTICS
KVSR SIDDHARTHA COLLEGE
OF PHARMACEUTICAL

contents
Introduction
Classification
Factors affecting circadian rhythms
Chronotherapeutic drug delivery systems
Applications
Importance
Limitations

Introduction
 Drug absorption, distribution, metabolism, and elimination
are influenced by many different physiological functions of the
body which may vary with time of the day.
 The PK parameters characterizing these different steps,
conventionally considered to be constant in time, depend on
the moment of drug administration.
 How ever, the time of day has to be regarded as an additional
variable influencing the kinetics of a drug since many drugs
are affected by time of administration and the activity or rest
period of the human or animal.
 Chronokinetic studies have been reported for many drugs in
an attempt to explain chronopharmacodynamic phenomenon
and demonstrate that time of administration is a possible
factor of variation in the kinetics of the drug.

What is
chronopharmacokinetics…
 Chronopharmacokinetics investigates the variation in drug
plasma levels as a function of time of day and the
mechanisms responsible for time dependant variations.
 It deals with the study of the temporal changes in absorption,
distribution, metabolism and elimination.

What is the aim of
the
chronopharmacokineti
cs
 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 least toxic
or totally safe for body.

When do we need
chronokinetic studies?
 When possible daily variations in pharmacokinetics may be
responsible for time dependant variations in drug effects.
 When drugs have a narrow therapeutic range.
 When symptoms of a disease are clearly circadian phase-
dependant (ex: nocturnal asthma, angina pectoris, ulcer etc.)
 When drug plasma concentrations are well correlated to the
therapeutic effect in case the latter is circadian-phase
dependant.
 When the drug has some serious adverse effects that can be
avoided or minimized because there are related to time of
administration ( ex: amino glycosides nephrotoxicity)

Reasons for
chronopharmacokineti
cs
 The time dependant changes are probably due to circadian
variation in GIT.
 It may also be due to variations in levels of various metabolic
enzymes such as cytochrome P450 (CYP 3A)

Body rhythms
These are the biological process that show cyclic variation over
time.
Types of body rhythms:
1) Circadian rhythms- which lasts for about one day. Ex: sleep
walking, body temperature.
2) Ultradian rhythms- which lasts for shorter than a day, like
seconds. Ex: heartbeat.
3) Infradian rhythms- which lasts for longer than a day, like
monthly rhythms- menstrual cycle.

Circadian
rhythms
Exogenous
rhythms
Sleep wake
cycles, blood
pressure, etc.
Endogenous
rhythms
ACTH output,
rapid eye
movement etc

classification
a) Physiologically induced
time dependency
1) Absorption- elimination parameters
2) Distribution and Plasma binding
3) Enzymatic metabolic activity
4)Systemic clearance
5)Renal clearance
6) CSF drug concentration
b) Chemically induced time
dependency
1) Auto-induction
2) Auto inhibition.
There are two types

1) Circadian changes in drug absorption
Absorption is altered due to circadian changes in:
 Gastric acid secretion
 pH
 Motility
 Gastric emptying time-longer for evening meal-tmax
 GI blood flow
 Routes of administration
 Absorption is also altered due to physicochemical properties- lipophilicity or
hydrophilicity.
Ex:
1) Most lipophilic drugs like phenytoin seems to be absorbed faster when the
drug is taken in morning compared with the evening.
2) NSAIDs- indomethacin and ketoprofen has better absorption in the morning
and greater bioavailability.
3) Skin penetration of a eutectic mixtures of lidocaine and prilocaine depend on
time of administration with higher penetration rate in evening.
a) Physiologically induced time dependency

2) Circadian changes in drug distribution
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 glyco
protein are time dependant and occurs early in the afternoon when
compared during the night.
Ex:
1) Cis- diamine dichloro platinum (cis DDP)- anti- neoplastics - maximum
binding to plasma proteins is in afternoon and minimum in the morning.
2) Drug concentration of free fraction of phenytoin and valproic acid have
been found to vary in 24 hrs scale.

3) Circadian changes in drug distribution
Metabolism is altered due to circadian changes in
 liver
 Cytochrome p-450 monooxygenase ex: hydrocortisol
 Hepatic blood flow
 First pass elimination of drugs.
 Enzyme activity
 Temporal variation in oxidase activity of the liver and conc. Of microsomal
enzyme at the beginning of activity.
 Temporal variation in conjugation i.e. hepatic glucuronidation and
sulfation ex: paracetamol.
Limitations of the metabolism:
 Capacity limited metabolism results in decreased hepatic clearance in case
of phenytoin
 Enzyme induction causes hepatic clearance of carbamazepine
 Decreased hepatic blood flow causes hepatic clearance of propranalol

4) Time dependency in systemic clearance
 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: Ethosuximide, valproic acid, carbamazepine and clonazepam.
5) Circadian changes in kidney drug
Excretion is altered due to circadian changes in :
 Glomerular filtration
 Renal blood flow
 Urinary pH – change in urinary pH decreases the clearance in case of
salicylic acid
 Tubular reabsorption- increase in reabsorption increases the clearence in the
case of ascorbic acid
 Urine output and
 Urinary excretion of electrolytes.
All these are lowered during the resting period than in activity period

Acidic drugs are excreted faster after evening administration
ex: sodium salicylate and sulfasymazine.
6) Time dependency in cerebrospinal fluid (CSF)
drug concentration
 The drug concentration will be maximum during the dark period ( 2:00 –
5:00 am)
 It will be minimum during the light period (14:00 – 17:00 pm)

b) Chemically induced time dependency
1) Auto induction
Induction of enzymes by the drug is responsible for elimination there by
increase the clearence of the drug.
Ex: repeated doses of carbamazepine, rifampicin induces the enzymes
responsible for their elimination.
2) Auto inhibition
The metabolites formed increase in concentration and further inhibit
metabolism of the parent drug.
Ex: xanthine oxidase inhibitor- allopurinol, verapamil.

Factors affecting circadian
rhythms
• Food
• Meal timing
• GI pH
• Intestinal motility
• Digestive secretions
• Intestinal blood flow
• Light
• The timing of exposure to light
• The length of exposure
• Intensity and wavelength of light

PHASE RESPONSE CURVE

Drugs that undergo
chronokinetics
Class of
drugs
Examples
Antibiotics Amino glycosides,
Amikacin
General
anesthetics
Benzodiazepines,
Halothane
NSAIDs Indomethacin,
ketoprofen
Anticancer
drugs
5-fluoro uracil,
Cisplatin

Circadian rhythms and severity
of clinical disease

Applications

Chronotherapeutic drug delivery
systems
 Enteric coatings
 Layered systems
 Time controlled explosion systems(TES)
 Sigmoidal release systems(SRS)
 Press-coated systems

Enteric coated tablets
Layered tablets
Time controlled explosion systems (TES)

Importance
 Diseases like angina pectoris, ulcerous conditions, asthma,
cardiac disorders etc. are in such states where symptoms are
manifested in circadian rhythms and chronopharmacokinetic
studies, find themselves as important tool to decide the moment
of administration.
 When the drug has some severe adverse effects related to the
time of their administration ex: nephrotoxicity associated with
amino glycosides.
 These studies are needed in knowing pharmacokinetic data
of drugs, the toxic effects of which can be eliminated or
minimized by altering the time of administration.

Limitations
Experimental difference between species
rodents and humans
Harmful to rodents or experimental animals.
Large number of animals are required
Very complex during anti cancer drug
development.

Conclusion
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 dependant pharmacokinetics can sometimes be
responsible for daily variation drug effects or adverse effects.
Hence time of day should be considered as an additional
variable that influences the kinetics of the drug.
Drug release pattern if designed in a time controlled manner,
maximum drug can be available at peak hours with minimum
side effects of toxicity.

References
 Applied bio-pharmaceutics and pharmacokinetics by
Leon.shargel.
 Biopharmaceutics and pharmacokinetics by Venkateswarlu
 www.pharmainfo.net
 http://www.ncib.nlm.nih.gov/pubmed/18248311
 www.authorstream.com

Thank you…
