23-02-2013, 10:00 AM
CHRONOPHARMACOKINETICS
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INTRODUCTION TO CHRONOPHARMACOKINETICS
Adsorption distribution, metabolism, and elimination are influenced by many different physiological functions of the body, which may vary with time of the day . Thus , the pharmacokinetics parameter characterizing these different steps ,conventionally considered to be constant in time ,depend on the moment of the drug administration . Time of day has to be regarded as an additional variable influencing the kinetics of the drug.
time dependent changes in kinetics may proceed from circadian variations at each step e.g. adsorption , distribution, metabolism and elimination .Thus, circadian variations in gastric acid secretion and pH.motility , gastric emptying time , gastrointestinal blood flow , drug protein binding , liver enzyme activity and or hepatic blood flow, glomerular filtration, renal blood flow,urinary pH .and tubular reabsorption may play a role in such kinetic variations.
PHYSIOLOGICALLY-INDUCED TIME DEPENDENCY
The physiologically induced time dependency may be grouped into following categories.
Absorption-elimination parameters
distribution
plasma binding
CSF drug concentration
Enzymatic metabolic activity
System clearance
Renal clearance
TIME DEPENDENCY IN ABSORPTION- ELIMINATION PARAMETERS
This category includes studies involving oral drug administration , generally gives as a single dose at various fixed time
The parameter measures represent hybrid of adsorption and elimination such as peak time and peak concentration
Temporal variations in drug absorption and the role of food intake and its timing
with regard to chronokinetics and the oral route of drug administration , it is critical to determine what role can be attributed to the presence or absence of nutrients in the digestive tract.
The duration of gastric emptying was greater for the evening meal than the morning
THE DEPENDENCY IN DRUG DISTRIBUTION
Circadian rhythm in membrane permeability have been cited for many years as a governing of the biological clocks.
The time dependency of the passage of drugs in to red blood cells also provided a strong argument for the existence of temporal variations in the passage of drugs through biological membranes for which RBC are often chosen as a model
Bruguerolle performed round the clock into vitro permeability studies of lidocatine , a local anesthetic using human red blood cell , as a membrane model . The lidocaine content of the erythrocytes sampled at 22 hours was 74% of the plasma concentration , while it was only 48% when sampled at 10 hours
TIME DEPENDENCY IN PLASMA PROTEIN BINDING
In humans beings most plasma protein , such as albumin and acid alpha-I-glycoprotein which are rather highly involved in drug transport , exhibit circadian rhythmicity
Rhythms in these plasma constituents are independent of that of the plasma hematocrit and presumably reflect the 24hour pattern of protein production by the liver, rather than that of body fluids.
Although the difference between the diurnal crest and the nocturnal through in protein concentration amounts to only10% in young adults , it may be as greater as 20% in elderly..
TIME DEPENDENCY IN CEREBROSPINAL FLUID (CSF) DRUG CONCENTRATION
Plasma and CSF concentration of valproic acid were monitored simultaneously in a group of 6 rhesus monkeys during constant rate intravenous infusion of the drug.
The time course of CSF concentration showed the existence of a diurnal cycle.
They paralleled plasma concentration with maxima during the dark period (02.00-0.500hours) an minima during the light period(14.00-17.00hours).
The ratio of maximum minimum concentration ranged from 1.31 to 1.42 for plasma and 1.35 to 1.81 for CSF.