SEMINAR ON

CHRONOPHARMACOKINETICS

Visit
www.bpharmstuf.com
For more ppt’s & material
 CONTENTS
 Introduction  Factors affecting
circadian rhythms
 Definitions
 Applications
 Scope
 Drugs that undergoes
 Dtermination of chronokinetics
circadian rhythms
 Conclusion
 Classification
 References

www.bpharmstuf.com
Introduction:
 Study of the temporal changes in ADME

 The influence of time of administration

 Homeostasis

 Non-cyclical change

 “Non-linear pharmacokinetics”
www.bpharmstuf.com
Definitions:
 Chronopharmacokinetics
 Biological rhythm
 The Period (T)
 The Acrophase (Ø)
 The Amplitude (A)
 The Mesor (M)
 The Frequency (F)

www.bpharmstuf.com
www.bpharmstuf.com
 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
www.bpharmstuf.com
www.bpharmstuf.com
 Diurnal variations
 Noctutnal variations
 Synchronisation
 Chronobiology
 Chronopharmacology
 Chronopharmacodynamics
 Chronotherapy

www.bpharmstuf.com
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.

www.bpharmstuf.com
When we need chronopharmacokinetics:

 Daily variations in pharmacokinetics

 Narrow therapeutic range

 Symptoms of a disease - circadian phase-

dependent

www.bpharmstuf.com
Classic phase markers:

 Melatonin secretion by the pineal gland

 Core body temperature.

www.bpharmstuf.com
Classification
 Physiologically-induced time dependency

 Chemically-induced time dependency

www.bpharmstuf.com
 Physiologically-induced time
dependency:

:
Absorption-elimination parameters
 Distribution
 Enzymatic metabolic activity
 Systemic clearance
 Renal clearance
 CSF drug concentration
 Plasma binding

www.bpharmstuf.com
 Circadian changes in drug
absorption:
 Gastric acid secretion

 pH

 Motility

 Gastric emptying time – longer for evening meal –

tmax

 Gastrointestinal blood flow

www.bpharmstuf.com
 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

www.bpharmstuf.com
 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

www.bpharmstuf.com
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

www.bpharmstuf.com
Circadian changes in drug metabolism:

 Liver

 Cytochrome p-450 monooxygenase

 Chronobiological variations

 First pass elimination of drugs

www.bpharmstuf.com
 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 www.bpharmstuf.com
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

www.bpharmstuf.com
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

www.bpharmstuf.com
 Circadian changes in kidney drug
excretion:
 Glomerular filtration,
 Renal blood flow,
 Urinary pH,
 Tubular reabsorption,
 Urine output, and
 Urinary excretion of electrolytes.

www.bpharmstuf.com
Ex: The rhythmicity in urinary pH

modifies drug ionization

 Acidic drugs are excreted faster after evening

administration
Ex: Sodium salicylate and Sulfasymazine

www.bpharmstuf.com
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)

www.bpharmstuf.com
Chemically induced time dependency:

 Auto induction:
Ex: Carbamazepine, Rifammpicin etc..

 Auto inhibition:
Ex: Xanthine oxidase inhibitor - allopuriniol

www.bpharmstuf.com
Factors affecting circadian rhythms:
 Food
 Meal timing
 Gastrointestinal pH
 Intestinal motility
 Digestive secretions
 Intestinal blood flow
 Light

www.bpharmstuf.com
 The timing of exposure to light

 The length of exposure

 Intensity and wavelength of light

www.bpharmstuf.com
Phase response curve:

www.bpharmstuf.com
Other factors:

 Physical activity
 Music
 Administration of the neurohormone
melatonin
 Feeding schedules
 Temperature
 Pharmacology
 Sexual stimuli
 Stress
www.bpharmstuf.com
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
www.bpharmstuf.com
 Cancer

 Hypertension
higher concentrations early morning

www.bpharmstuf.com
Drugs that undergo chronokinetics:
 Antibiotics – Aminoglycosides,

 Antihypertensive drugs – Propranolol,

Nifedipine

 Anti epileptic drugs - Valporic acid

 Anti cancer drugs – Cyclosporine, Methotrexate

 NSAIDs – Ketoprofen, Indomethacin

www.bpharmstuf.com
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

www.bpharmstuf.com
www.bpharmstuf.com
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
  www.bpharmstuf.com
 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.

www.bpharmstuf.com
www.bpharmstuf.com
www.bpharmstuf.com