SEMINAR ON CHRONOPHARMACOKINETICS

CONTENTS

Introduction Definitions

Factors affecting circadian rhythms Applications

Scope

Dtermination of circadian rhythms

Drugs that undergoes chronokinetics

Conclusion References

Classification

Introduction:

Study of the temporal changes in ADME The influence of time of administration

Homeostasis
Non-cyclical change Non-linear pharmacokinetics

Definitions:
Chronopharmacokinetics Biological rhythm The Period (T) The Acrophase () The Amplitude (A) The Mesor (M) The Frequency (F)

Circadian rhythms:
- Exogenous rhythms Ex: Sleep wake cycles, blood pressure, pulse rate, metabolic, gastro intestinal rhythms - Endogenous rhythms Ex: ACTH output, corticosteroid output, . circulating neutrophils , circulating eosinophils , rapid eye movement

Diurnal variations Noctutnal variations Synchronisation Chronobiology Chronopharmacology Chronopharmacodynamics Chronotherapy

Scope:
Control the time of administration Variations in plasma drug level as a function of time of day. Mechanism responsible for the time dependent variation.

When we need chronopharmacokinetics:

Daily variations in pharmacokinetics

Narrow therapeutic range Symptoms of a disease - circadian phasedependent

Classic phase markers:

Melatonin secretion by the pineal gland

Core body temperature.

Classification

Physiologically-induced time dependency Chemically-induced time dependency

Physiologically-induced time dependency: Absorption-elimination parameters :

Distribution Enzymatic metabolic activity Systemic clearance Renal clearance CSF drug concentration Plasma binding

Circadian changes in drug absorption:

Gastric acid secretion pH Motility Gastric emptying time longer for evening meal tmax Gastrointestinal blood flow

Physico chemical properties lipophilicity or hydrophilicity

Examples: 1. For lipophilic drugs (Phenytoin) faster absorption in the morning

NSAIDs Indomethacin and Ketoprofen better absorption in the morning and greater bioavailability. 3. Paracetamol extent of absorption is less at night
2.

Circadian changes in drug distribution:

Body size and composition

Blood flow to organs - Sympathetic and parasympathetic systems - Diurnal increases and nocturnal decreases in blood flow Plasma protein binding

Circadian changes in plasma protein binding of drugs:

Plasma protein binding - Albumin and 1 glycoprotein acid time dependent - Peak concentration around noon Example: cis-Diamine dichloro platinum (cis DDP) - Free cis-DDP plasma concentration may be greater after dosing in the early morning

Circadian changes in drug metabolism:

Liver Cytochrome p-450 monooxygenase Chronobiological variations

First pass elimination of drugs

Enzyme activity - brain, kidney, and liver. Ex: -Hydrocortisol cortisol - cytochrome CYP3A activity Hepatic blood flow - Indocyanine green (ICG) clearance

Temporal variation in oxidase activity of the liver Temporal variation in conjugation Parcetamol

Limitations of the metabolism:

Capacity limited metabolism - decreases hepatic clearance in case of Phenytoin. Enzyme induction - Carbamazepine hepatic clearance Decreased hepatic blood flow - Propranalol hepatic clearance

Contraindications: Mono oxygenase activities male and female rats Liver microsomal testosterone hydroxylase

Time dependancy 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

Circadian changes in kidney drug excretion:

Glomerular filtration, Renal blood flow, Urinary pH, Tubular reabsorption, Urine output, and Urinary excretion of electrolytes.

Ex: The rhythmicity in urinary pH modifies drug ionization Acidic drugs are excreted faster after evening administration Ex: Sodium salicylate and Sulfasymazine

Time dependency in cerebrospinal fluid (csf) drug concentration:

Maxima during the dark period (02.00 05.00 am hours) Minima during the light period (14.00 17.00 pm hours)

Chemically induced time dependency:

Auto induction: Ex: Carbamazepine, Rifammpicin etc..

Auto inhibition: Ex: Xanthine oxidase inhibitor - allopuriniol

Factors affecting circadian rhythms:

Food Meal timing Gastrointestinal 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:

Other factors:
Physical activity Music Administration of the neurohormone melatonin Feeding schedules Temperature Pharmacology Sexual stimuli Stress

Applications:

Asthma - Nocturnal worsening of asthma is a serious clinical problem - Evening Theophylline and -agonist bronchiodilator

Peptic ucelr - morning - evening antagonist

proton pump inhibitor H2 receptor

Cancer Hypertension higher concentrations

early morning

Drugs that undergo chronokinetics:

Antibiotics Aminoglycosides, Antihypertensive drugs Propranolol, Nifedipine Anti epileptic drugs - Valporic acid Anti cancer drugs Cyclosporine, Methotrexate NSAIDs Ketoprofen, Indomethacin

Limitation of time dependent pharmacokinetics:

Difference between species rhodents and humans Harmful to rhodents/experimental animal Large number of animals

Very complex - anti cancer drug development

REFERENCE:

Time dependent pharmacokinetics by Rene H. Levy, Department of pharmaceutics BG-20, University of Washington, Seattle, Washington, U.S.A, pp. 115-127. Pharmacology, 6th edition, by H.P. Rang, M.M. Dale, J.M. Ritter and R.J. Flower, pg no. (98-126). Time dependent pharmacokinetics - recent developments by Rene H. Levy and C.R. Banfield University of Washington, Seattle, Washington. Pg no. (178-186). Applied Biopharmaceuticals & Pharmacokinetecs (5th edition) by Leon Shargel, page240-242

Drug disposition & pharmacokinetics Stephen H. Curry, 122 page. Daily Variationsin Ceftriaxone Pharmacokinetics in Rats. Antimicrob. Agent and chemother. M. Rebuelto, L. Ambros, and M. Rubio.2003. Clinical Concepts and Applications, 2nd addition, by Rowlend and Towzer, pp (256-262). www.pubmed.com www. Sciencedirect. com Bruguerolle B, Lemmer B.1993. Recent advances in chronopharmacokinetics: methodological problems. Life Sci. 52:1809-24.