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SEMINAR ON CHRONOPHARMACOKINETICS
CONTENTS Introduction
Definitions
Scope
Dtermination of circadian rhythms
Classification
Factors affecting circadian rhythms
Applications
Drugs that undergoes chronokinetics
Conclusion
References
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 (Ø) 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 phase-dependent
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
2. NSAIDs – Indomethacin and Ketoprofen better absorption in the morning and greater
bioavailability.3. Paracetamol – extent of absorption is less at
night
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 α1 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: β-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 β-agonist
bronchiodilator
Peptic ucelr - morning proton pump inhibitor
- evening H2 receptor antagonist
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.