Chronopharmacokinetics

about time dependant pharmacokinetics

1. CHRONOPHARMACOKINETICS or time dependant pharmacokinetics BY SAHITHI GADDE (Y13MPPC140003) DEPARTMENT OF PHARMACEUTICS KVSR SIDDHARTHA COLLEGE OF PHARMACEUTICAL SCIENCES

2. contents Introduction Classification Factors affecting circadian rhythms C hronotherapeutic drug delivery systems Applications Importance Limitations

3. 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.

4. 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 .

5. What is the aim of the chronopharmacokinetics 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 .

6. 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)

7. 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 )

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. 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.

9. classification There are two types

10. 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: Most lipophilic drugs like phenytoin seems to be absorbed faster when the drug is taken in morning compared with the evening. NSAIDs- indomethacin and ketoprofen has better absorption in the morning and greater bioavailability. 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

11. 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: Cis- diamine dichloro platinum (cis DDP)- anti- neoplastics - maximum binding to plasma proteins is in afternoon and minimum in the morning. Drug concentration of free fraction of phenytoin and valproic acid have been found to vary in 24 hrs scale.

12. 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

13. 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

14. 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)

15. b) Chemically induced time dependency 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 .

16. 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

17. PHASE RESPONSE CURVE

18. 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

19. Circadian rhythms and severity of clinical disease

20. Applications

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

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

23. 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.

24. 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.

25. 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.

26. 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

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