CHRONOPHARMACOKINETICSOR

TIME DEPENDANT PHARMACOKINETICS

BYSAHITHI GADDE(Y13MPPC140003)

DEPARTMENT OF PHARMACEUTICS

KVSR SIDDHARTHA COLLEGE OF PHARMACEUTICAL SCIENCES

contents

IntroductionClassificationFactors affecting circadian rhythmsChronotherapeutic drug delivery

systemsApplicationsImportanceLimitations

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 chronopharmacokinetics

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 clearance5)Renal clearance

6) CSF drug concentration

b) Chemically induced time dependency

1) Auto-induction2) Auto inhibition.

There are two types

1) Circadian changes in drug absorptionAbsorption 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 distributionDistribution 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: ᵝ 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 drugExcretion 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 inductionInduction 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 inhibitionThe 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 coatingsLayered systemsTime 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 humansHarmful to rodents or experimental animals.Large number of animals are requiredVery 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/1824831

1 www.authorstream.com

Thank you…