1. BIOAVAILABILITY OF DRGS THAT FOLLOW
NONLINEAR PHARMACOKINETICS
PRESENTED BY
N.VENUGOPAL
PHARMACEUTICS
ROLL-NO-24
&
CHRONOPHARMACOKINETICS

2. CONTENTS:
 INTRODUCTION
 BIOAVAILABILITY OF DRUGS THAT FOLLOW NON-LINEARPHARMACOKINETICS
 DEFINITION OF CHRONOPHARMACOKINETICS
 BODYRHYTHMS
 DESIGN OF A CHRONOPHARMACOKINETIC STUDY
 CIRCADIAN DEPENDENCE OF DRUG
PHARMACOKINETICS
 CONCLUSION
 REFERENCE

3. INTRODUCTION:
In some instances,the rate process of a
drug’s ADME are dependent upon carrier or enzymes that are
substrate specific,have definite capacities,and susceptible to saturation
at high drug concentration.
In such cases,an essentially first order kinetics transform into a
mixture of first order and zero order rate processes and the
pharmacokinetic parameters change with the size of the administered
dose.
The pharmacokinetics of such drugs are said to be dose-dependent.
Other terms synonymous with it are mixed-order,nonlinear
and capacity-limited kinetics.

4. BIOAVAILABILITY OF DRUGS THAT FOLLOW
NONLINEAR PHARMACOKINETICS:
The bioavailability of drugs that follow nonlinear
pharmacokinetics is difficult to estimate accurately.
 Each process of drug absorption, distribution, and
elimination is potentially saturable.
 Drugs that follow linear pharmacokinetics follow the principle
of superposition .
 The assumption in applying the rule of
superposition is that each dose of drug superimposes on the
previous dose

5.  An example of a drug with dose-dependent absorption is
chlorothiazide.
 The extent of bioavailability is generally estimated using [AUC].
 If drug absorption is saturation limited in the gastrointestinal
tract, then a smaller fraction of drug is absorbed systemically
when the gastrointestinal drug concentration is high.
 A drug with a saturable elimination pathway may also have a
concentration dependent AUC affected by the magnitude of Km
and V max of the enzymes involved in drug elimination .

6.  At low Cp, the rate of elimination is first order, even at the
beginning of drug absorption from the gastrointestinal tract.
As more drug is absorbed, either from a single dose or after
multiple doses, systemic drug concentrations increase to levels
that saturate the enzymes involved in drug elimination.
Drug concentrations increase to levels that saturate the
enzymes involved in drug elimination.
 The body drug clearance changes and the AUC increases
disproportionately to the increase in dose.

7. CHRONOPHARMACOKINETIC
S:
 Chronopharmacokinetics decribe the changes in
drug absorption,distribution,metabolism and or
elimination due to normal physiological circadian
rhythms.

8. BODY RHYTHMS
 These are the biological process that show cyclic
variation over time.
TYPES OF BODY RHYTHMS
 CIRCADIAN RHYTHMS
which lasts for about one day,like
-sleep walking rhythm
-the body temperature

9. ULTRADIAN RHYTHMS
shorter that a day,few seconds like
-heart beat
INFRADIAN RHYTHMS
longer than a day,like
-monthly rhythm-menstrual cycle
-yearly rhythm –bird migration

10. CIRCADIAN CLOCK SHOWING EFFECTS OF
BODY RHYTHMS ON PHYSIOLOGICAL
PROCESSES.

11. DESIGN OF A
CHRONOPHARMACOKINETIC STUDY
In a chronopharmacokinetic study many factors of variation must
be controlled :
• factors related to drug itself:
influence of food,
galenic formulation,
drug interactions
• subject related factors:
age,gender,pathology,
posture,exercise
• factors related to conditions of administration:
single or repeated dosing
constant rate delivery
route of administration

12. There are some instances in which a
chronopharmaco- kinetic study is needed:
• When possible daily variations in
pharmacokinetics may be responsible for time
dependent variations in drug effects.
• When drugs have a narrow therapeutic index
• When symptoms of a disease are clearly
circadian phase dependent e.g.(nocturnal asthma,
angina pectoris,
myocardial infarction,ulcer.)

13. CIRCADIAN DEPENDENCE OF DRUG
PHARMACOKINETICS
ABSORPTION
is altered by circadian (rhythms) like
changes in -gastric emptying time
-GI blood flow
-gastric acid secretion and pH.
most LIPOPHILIC drugs seems to be absorbed faster
when the drug is taken in the MORNING compared with
the evening.
e.g: absorption of VALPROIC ACID larger in the
morning than in the evening.

14. Absorption by other routes of administration may also
be influenced by biological rhythms.
For instance,in children,the skin penetration of an
eutectic mixture of lidocaine and prilocaine was reported
to depend on the time of aministration,with a higher rate
of penetration occuring in the evening.
In addition,circadian dose administration
timedependency in the forearm skin penetration of
hydrophillic methylnicotinate and lipophillic
hexylnicotinate was recently demonstrated.
Circadian variations have also beeen reported in the
occular absorption of topically applied timolol.

15. DISTRIBUTION
It is altered by circadian changes in
-bodysize 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 the night.
 circadian variations in the drug protein binding of
acidic and basic drugs have been reported both in
humans and animal studies.
e.g: free plasma concentrations for anticonvulsant drugs
such as carbamazepine,diazepam,phenytoin and valproic
acid,and for antineoplastic drugs such as cisplatin have

16. been documented,these changes are usually reported to be
dependent on temporal variations in plasma protein
levels,which are circadian-time dependent.
The time dependency of the passage of drugs into red
blood cells also provides a strong argument for the
existence of temporal variations in the passage of drugs
through biological membranes,for which red blood cells
are often used as a model.

17. METABOLISM
Hepatic drug metabolism is generally assumed to
depend on liver enzyme activity and or
hepatic blood flow.
Both have been shown to be circadian time-dependent.
Circadian variations in enzyme activity were
documented in the liver,kidney and brain,however these
data were obtained in animals and no direct data on
enzyme activity have been reported in humans.
 For drugs with a high extraction ratio,hepatic
metabolism depends on hepatic blood flow.

18.  several experimental and clinical pharmacological
studies have indirectly investigated temporal variations
in hepatic drug metabolism capacity by evaluating the
chronokinetics of drugs and their metabolites,even if not
pharmacologycally active.
Thus conjugation,hydrolysis,and oxidation were shown
to be circadian timedependent.
As far as metabolic phenotype is concerned,the effect
of diurnal variation on debrisoquine metabolic
phenotyping,with the slowest rate of metabolism
occuring dring the day time.

19. ELIMINATION
Most drugs are eliminated via the kidneys.
Glomerular filtration,
Renal blood flow,
Urinary pH and
Tubular resorption
have all been shown to be circadian time
dependent,with higher values during the day time in
humans.Thus,the urinary excretion of many drugs may
depend on these rhythmic variations.

20.  Renal elimination depends partially on the
ionisation of drugs,and thus may be modified by
temporal changes in urinary pH.
This has been described for acidic drugs such as
sodium salicylate and sulfasymazine,which are excreted
more quickly after evening than morning
administration.

21. CONCLUSION
 Chronopharmacokinetics is a successful tool
in the hands of clinical pharmacist ,which if
judiciously exploited can help in better
therapeutic drug monitoring,thus reducing side
effects and providing better patient care.

22. REFERENCE
 Biopharmaceutics and pharmacokinetics by
D.M.Brahmankar and Sunil B.Jaiswal,page
no(273).
 Biopharmaceutics and pharmacokinetics Second
edition by V.Venkateshwarlu,page no(355-360).
 Applied Biopharmaceutics and
Pharmacokinetics,fifth edition by Leon
Shargel,page no(295-299).
 International Journal of Pharmacy and
Pharmaceutical sciences,vol-4,Issue
4,2012,Review Article.