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CHRONOPHARMACOKINETICS ADMINISTRATION,
TIME DEPENDENT EFFECTS OF DRUGS WITH DIFFERENT DISEASES

ABSTRACT

Rajesh Gollapudi1*, Harika Javvaji1, Vanaja Arpineni3, and Rama Rao Tadikonda2
1.
Department of Pharmaceutics, K.L.R. Pharmacy College, Paloncha, Andhra Pradesh., India.
2.
Bluebirds Instititute of Pharmaceutical Sciences, Hamakonda, Andhra Pradesh., India.
3.
Pulipati Prasad college of pharmaceutical sciences, Khammam, Andhra Pradesh., India.

Chronopharmacokinetics is derfined as the predictable rhythamical changes dependent on the time of dosing.
Absorption ,
distribution , metabolisam and elimination are influenced by many different physiological functions
of the body which may vary with time of day. Thus the pharmacokinetic parameters charecterising these different
steps conventionally considered to be constant in time depend on the moment of drug administration. Time of day
has to be regarded as an additional variable influenceing the kinetics of a drug. These studies have been reported for
many drug in an attrempt to explain chronopharmacodynamic phenomenon and demonstrate that the time of
administration is a possible factor of variation in the kinetic of a drug. In this paper this is illustrated with the
chronopharmacokinetics of cardiovascular drugs (-blockers, calsium channel blockers, A.C.E inhibitors), NSAIDS,
peptic ulcer drugs , asthma drugs and antibiotics. Time dependent changes in kinetics may proceed from circadian
variations at absorption, distribution, metabolism, and elimination.Thus circadian variation in GIT, drug protein
binding, hepatic, and in urinary tract.
Keywords: Chronopharmacokinetics, Circadian rhythm ,Chronopharmacodynamics, Bioavailability.

INTRODUCTION
Chronopharmacokinetics is defined as the predictable
rhythamical changes dependant on the of dosing.
Absorption, distribution, metabolism, and elimination are
influenced by different physiological functions that may
vary with the of dosing.The of administration of a drug or
toxic agent may influence the response of the
organism.Chronopharmacology examines the influence
of the momentum of drug administration and body
response according to the temporal structure of
organism.Chronokinetic studies have been reported in
human and animals in order to explain
chronopharmacodynamic phenomenon and demonstrate
that time of drug administration influences the kinetics of
drug. Time dependent changes in kinetics may proceed
from circadian variations at each step eg: Absorption,
distribution, metabolism, and elimination.
Circadian rhythms are endogenous in nature driven by
Oscillators or Clocks and persist under free running
conditions. The rhythm in human body temperature which
is timed by the biological clocks has an about 25 hours
period under free running conditions. Thus circadian
variations in gastricacid secretion and PH, motility, gastric
emptyingtime, gastrointestainal bloodflow, drugprotein
binding, liver enzyme activity, hepatic bloodflow,
glomerular filtration, renal bloodflow, urinary PH, and
tubular reabsorption may play a role in such kinetic
variations.
New tools such as new formulation procedures or pumps
with or constant or programmable deiivery rates ,now
make a possible to deliver a drug at a definite time or
during a span of time and at a controlled rate in
chronokinetic studies.

Chronopharmacokinetics of cardiovascular
drugs: blockers
Chronopharmacokinetics of cardiovascular drugs such as
nifedapine and propranalol having high cmax and lower
tmax in after morning compared to evening administration
. These kinetic variations were not detected by using
sustained release dosage forms.
Ex: Nifedapine and isosorbidemono nitrate
These two drugs are sustained release dosage forms but
these are not given the kinetic variations because these
two are liphophilic drugs. The differences in
chronopharmacokinetics can be estimated by taking one
liphophilic drug and another one is hydrophilic drugs can
be administered in hypertension patients.
Liphophilic beta blocker - Propranolol
Hydrophilic beta blocker - Atenolol
Propranolol shows better result but not Atenolol because
propranolol is absorbed more rapidly after morning
administration compared to evening.The rate of
absorption of liphophilic drugs is faster than hydrophilic
drug after the morning dosage in humans.
Liphophilic drugs are absorbed faster when the drug is
taken morning compared to evening administration.
(Ramon C.Hermida)
Ex: The kinetics of valpropicacid depending on morning
or evening administration under used life condition (light
meal at break fast, heavy meal at dinner). The same meal
condition

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(same size and content of breakfast and dinner) were
applied. There is no significant circadinan changes
between morning and evening administration because
timing of drug administration with respect to meal is a
common consideration in a drug prescription.
Other route of administration may also be influenced
by biological rhythms
Ex: In childrens, the skin penetration of an eutetic
mixture of lignocaine and prilocaine penetration are
depending on time of administration . The higher rate of
penetration occurring in the evening.

Drug delivery at definite time via different

formulations
Drug delivery at definite time according to its time of
administration sustained release forms deliver the potential
to obtain a maxmimal blood concentrations at a definite
time from the time of administration.
Ex: Sedative drugs must be given at night.
The Chronokinetic differences demonstrated for standard
drug formulation may not be observed for the same drug
when presented as sustained release formulation.
Ex: An I.R form of isosorbide mononitrate is given to
healthy persons in morning this drug having faster
absorption in morning when compared to evening
administration. This type of absorption changes are not
observed in S.R formulation of isosorbidemononitrate .but
this type of absorption changes are obtained with an
immediate release and sustained release dosage form
of nifedapine . Which was given in transdermal systems
(patches) also involves chronopharmacological
phenomenon in this route of administration provides
constant and continious delivery of drug.

Calsium channel blockers

Differential effects of morning vs evening administration
of calsium channel blockers .
Ex: Amlodipine, clinidipine, diltiazem.
Diltiazem is more effecting in controlling the blood
pressure 24. This drug is sustained release formulation
and which is administered at night and also reduce diurinal or
nocturinal B.P.
Dihydropyridine derivatives also reduce the B.P during
day and night time independently on time of dosing.
Nitrendipine is administerd in the early morning (6am) at
that time produce the higher action to reduce the B.P.
The same amount of Nitrendipine is administerd in the
evening at that time increase diurinal or nocturinal ratio.
Evening time administration of isradipine is best when
compared to morning time of administration. Which is
reduce the sleep time in systolic and diastolic B.P.

(Portaluppi ett al,). Which is effectively reduce the 24 hr

systolic B.P and diastolic B.P in dipping chronic renal
failure patients in evening time when compared to morning
time.

A.C.E inhibitors
Trandolapril is administered in the just before going to
bed and morning. The bed time of administration was
found to be safe and effective when compared to morning
in hypertensive patients. Ramipril is more effectively
reduce the day time B.P when it is administered morning
and more effectively reduce the night time B.P when it is
administered in the evening . Sprirpril shows the action
slightly higher with morning dose reduse in the 24 hr meal
systolic B.P and diastolic B.P compared to bed time dose
(Hermida et al.,) Which is the once daily formulation
because it is having extended duration of action due to its
long elimination half life about 40 hrs .

Chromopharmaco kinetics of NSAIDS

Phisiological functions of the body exhibit circadian
rhythms.
Ex:-Gastric acid secretion, G.I blood flow, liver and renal blood
flow.
These all effect on the pharmaco kinetic behaviour of
drugs.
1.Non steroid anti inflammatory drugs are having greater
rates and contents of bioavailability when administered in
the morning than evening.(clench et.al;1981).
Ex:- Indome thacin and ketoprofen.
It has been suggested that day time absorption of the
drugs is bertter than night time absorption. Circadian
changes in renal function or hepatic blood flowmay also
explain temporal variations in drug plasma levels. (Brugulle
and Lemmar et.al;1993).
Another important factor concerning timing of dosing is
the effect on the absorption. The first objective of the
study report here was to investigate whether ibuprofen
pharmacokinetics varied with time in healthy humans. Two
formulations, a conventional hard gelatin capsule and a
press-coated time controlled release tablets were
administered under fasting conditios in the morning and
evening.
In the first step ibuprofen capsules (300 mg) and three
press coated tablets (300 mg) administered in subsequent
stage (Marikki Halsas et.al; (1999). These two
formulations were administered at 8.00 and 22.00
between morning and evening administration.
conditions has the opposite to that with the capsule
formulation.

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In the second step only press coated tablets were
admistered after 2hrs meal.
1.5, 2, 3, 4, 6, 8, 10 & 12 h after tablet administration.
Plasma was separated and stored at 20 C until analysed
by HPgh performance liquid chromatography. (Avgerinous
and Hutt 1986).
The chronopharmacokinetics behaviour of the presscoated ibuprofen tablet under fasting conditions has the
opposite to that with the capsule formulation. The peek
plasma levels was obtained signoificantly high in every
dose due to faster absorption. The extent of bioavailabuility
was significantly higher in the evening.
The bioavailability of ibuprofen undergoes only minimal
circadian variations markedly less than that of
ketoprofen or in Indomethacin.
Chronopharmacokinetic behavior of the press
coated Ibuprofen tablets administered under fasting

Chronopharmacokinetics of H2 blockers
Hz blockers are used in the treatment of peptic ulcers.
They should be taken once a day in the late after noon or
early night when acid secretion is increasing the
compound have a shorter or longer half-life (Moore et.al;
Ex:- Rantidin, Cimetidine, Farmotidine.
Rantidin is having less drug infusion in night time than
day time.
These H2 blockers are now drugs of first choice in the
treatment of peptic ulser disease. In 1970 Moore and
Englert first described the circadian rhythm in gastric acid
secretion in humans.

Chronopharmacokinetics of Anti-Asthmatic drugs

Asthma is attacked more frequently in night hours. Lungs
are more sensitive to broncho constrictor substances such
as Acetylcholine, Histamine, house mite dust, grass
propellers, at night time than day time. Nocturnal Asthma
is common in Asthmatic disease. It is treated by antiasthmatic drugs.
Ex:-Theophylline.
Theophylline is one of the first drug for daily varieties in
pharmacokinetics, which is having Cmax has lower and
Tmax has longer after evening administration than after
morning administration.
Theophylline must be given if higher doses during the night
time than day time. Single evening dose or higher evening
dose may be advantageous in treatment of nocturnal asthma.

In the treatment of asthmatic patients terbutaline is

remedies of first choice.
The pharmacokinetics of sympathomimetics terbutaline
effects on peak expiratory flow circadian phase
dependent. Which is giving upto 7 days in orally 7.5 mg
at 7:30 hrs and at 19:30 hrs. After 7 days Cmax has
higher in the morning than evening administration (BJORN
LEMENER et.al; 1996).
Meal timings and contents that the pharmacokinetics of
sustained release theophylline tablet formulations quite
different following morning than evening administration.
Sustained release theophyllihne medications exihibit a
shorter Tmax and greater Cmax when the dose
administered in the morning than evening. Bioavailability
of theophylline sustained release preparations once-a-day
found to three times increased when the dose is
administered in the evening when compared to morning.
Administration- time differs in drug kinetics occur in both
chilrens and adults but more in children when compared
to adults.

Chropharmacokinetics of Antibiotics
The administration time difference in the
pharmacokinetics of antimicrobial agents.
The pharmacokinetics of gentamicin exhibited similar
significant temporal variations in dogs administration of
dose at different times of day. The clearance of
gentamicin, amikacin, isepamicin was higher in the activity
period and longer serum half life and higher serum AUC
achieved at the begining of the day. The rate of urinary
excretion was very high. The effect of dietary protein
loading and circadian cycle of the pharmacokinetics of
gentamicin. Circadian variations in the pharmacokinetics
of gentamicin in human beings. Higher AUC between 8pm
and midnight. Longer serum half life (t ) between 8pm
and midnight. Lower renal clearance between 8pm and
midnight. Aminoglycosides induced higher toxicity when
the drug is injected in experimental animals during the
rest period compared to activity period. The role of
treatment time is relation to circadian rhythms is an
important factor modulating the effects of antimicrobial
drugs in humans.
Ex:- The afternoon administration of hepatitis B vaccine
produce higher antibodies compared to morning
administration. The daily variations in aminoglycosides
pharmacokinetics is the first factor food intake is the
second factor.

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CONCLUSION
The rate of absorption, distribution, metabolism, excretion
and bio-availability those are depending upon the time of
administration with food or witout food. This type of
discussion is present in this chronopharmacokinetics.
Pharmacokinetics can be significantly influenced by the
time of the drug administration.
Chronopharmacokinetics has clinical implications
moreover, chronokinetics can sometimes, be responsible
for daily variation in drug effects or adverse effects.
In healthy human body, various pathophysiologic process
occur only at certain times of day or specific interval of
time. Similarly it has been explained the different disease
conditions and treatments according to circadainrhythms.

inflammation, Advanced drug delivery reviews, 1981

(232-252).
5.Francesco Portaluppi, carlos calvo, chronotheraphy of
hypertension: Administration-time-dependent effects of
treatment on the circadian pattern of blood pressure,
Advance Drug Dolivery Reviews, 59 (2007) 923-939.
6.Michael H.Smolensky, Bjoern Lemmer, Alian
E.Reinberg, Chronobiology and chronotheraphy of
allergic rhinitis and bronchial asthma, Advanced Drug
Delivery Reviews 59 (2007) 852-882.
7. Michael H.Smolensky, Nicholas A.Peppas,
Chronobioloy,drug delivery and chronotherapeutics,
Advanced Drug Delivery Reviews, 59 (2007) 828-851.

Similarly it has been observed that the exacerbation of

8. Marikki Halasa, Janna Hietala, morning versus evening

diseases also follows a circadian rhythmic pattern with

dosing of ibuprofen using conventional and time-

the diseases shows peak and trough phenomenon,

controlled release formulations, international journal of

dosage forms can be designed in a time controlled

pharmaceutics, 189 (1999) 179-185.

manner so as to maximize the drug response and

9.Ramou C.Hermida and Diana.E.Ayala, chronotheraphy

minimize the side effects.

of hypertension : Administration-time-dependent effects

Finally it is well known that symptoms and the onset of

of treatment on the circadian pattern of blood pressure.

certain diseases predominate at certain times of the day,

Advanced Drug Delivery Reviews, 59 (2007) 923-939.

this implies that the timing of the drug treatment should

vary according to the symptoms observed. It is, therefore,
important to rigorously control factors that are known to
influence pharmacokinetic processes in chronokinetic
studies. Time of the day should be regarded as an
additional variable that influences the kinetics of the drug.

REFERENCES
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Address for Correspondence:

rajeshgollapudi@yahoo.com
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