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.