1. PRESENTED BY:
G.V.GOWTHAMI
256213886010
UNDER THE GUIDENCE:
Dr.SATYABRATA BHANJA
M.Pharm,Ph.D

2. NON-LINEAR PHARMACOKINETICS
 It is a Dose Dependent Pharmacokinetics.
 Nonlinear pharmacokinetic models imply that some
aspect of the pharmacokinetic behaviour of the drug is
saturable.

3. CAUSES OF NON-LINEARITY
 Saturation of enzymes in process of drug
ADME
 Pathologic alteration in drug ADME

4. EXAMPLES
 Amino glycoside may cause renal nephrotoxicity,
thereby altering renal drug excretion
 Obstruction of the bile duct to the formation of
gallstone will alter biliary drug excretion

5. PROCESS SATURATED
 Absorption
 Distribution
Metabolism
 Excretion

6. PROCESS USUALLY SATURATED
Metabolism
Active tubular secretion

7. GI absorption
CAUSE DRUG
Saturable gastric or GI
Decomposition
Penicillin G, Saquinavir
Saturable transport in gut wall Riboflavin, Gebapentin, L-dopa,
baclofen
Intestinal Metabolism Salicilamide, Propranolol
Low Solubility but high dose Chlorotiazide, griseofulvin, danazol.

8. Distribution
CAUSE DRUG
Saturable transport into/ out of
tissues
MTX
Saturable plasma protein binding Phenylbutazone, lidocaine, salicylic
acid
Cellular uptake Methicillin
Tissue binding IMI
CSF transport Benzylpenicillins

9. Metabolism
Cause Drug
Saturable metabolism Phenytoin, salicylic acid,
theophyllin, valproic acid
Enzymes induction Carbamazepine
Enzymes limitations PCT, alcohol
Altered hepatic blood flow Propranolol, verapamil
Metabolite inhibition Diazepam

10. Renal Excretion
Cause Drug
Active secretion Mezlocillin, p-aminohippuric acid
Tubular reabsorption Riboflavin, ascorbic acid,
cephapirin
Change in urine pH Salicylic acid, dextroamphetamine

11. Biliary Excretion
Cause Drug
Biliary secretion Iodipamide, sulfobromophthalein
sodium
Enterohepatic recycling Cimetidine, isotretinoin

12. MICHAELIS MENTEN EQUATION
 Nonlinear pharmacokinetics can be best described by Michaelis
Menten Equation.
-dc/dt=Vmax.c/Km+c
 Where:
 dC/dt : rate of decline in drug conc. with time
 Vmax : theoretical maximum rate of process
 Km: Michaelis constant

13. • When Km = C
• -dc/dt=Vmax/2
• When Km>>C
• -dc/dt=Vmax.c/Km
• When Km<<C
• -dc/dt=Vmax

15. Estimation of Km and Vmax
Integration of Michaelis Menten Equation
log C = log Co + (Co –C)–Vmax
2.303Km 2.303Km
Semilog plot of C vs t yields a curve with terminal linear portion,
which on back extrapolation to time zero give y intercept log Co.
log C = log Co –Vmax
2.303Km

17. Km and Vmax....……....contd.
At low plasma concentration:
(Co –C)/2.303 Km = log Co/Co
So Km can be obtained from this equation while Vmax can be
obtained from slope by putting value of Km.

18. Estimation of Km and Vmax (steady state)
In case of I.V. infusion a steady state concentration is maintained by a suitable
dosing rate (DR).
This DR at steady state equals rate of elimination.
So Michaelis Menten equation can be written: DR = Vmax . Css
Km + Css

19. LINEWEAVER-BURKE PLOT/KLOTZ PLOT:
 Taking reciprocal of equation:
 DR=Vmax .Css/Km+Css
1/DR = Km/Vmax.Css + 1/Vmax
A plot of 1/DR Vs 1/Vmax yields a straight line with slope
Km/Vmax and y-intercept 1/Vmax
1/DR slope=Km/Vmax
1/Vmax
1/Css

20. DIRECT LINEAR PLOT
 A pair of Css,1 and Css,2
obtained with 2 different
dosing rates DR1 and
DR2 is plotted.
 The points Css,1 and DR1
are joined to form a line
and a second line is
obtained similarly by
joining Css,2 and DR2.
DR
Vmax
DR1
DR2
Css,1 Css,2 Km
Css 0 Km

21. THIRD GRAPHICAL METHOD
 Estimating Km and Vmax involves rearranging the
following eq.
 DR=Vmax .Css/Km+Css
 Gives DR=Vmax-Km.DR/Css
 Km and Vmax can also be calculated numerically by
using following equations
 DR1=Vmax.Css,1/Km+Css,1 &
DR2=Vmax.Css,2/Km+Css,2
 By combining above equations
 Km=DR2-DR1
DR1/Css,1-DR2/Css,2

25. Km and Vmax (Steady state)....contd
Graphical Method
Plot between DR and DR/Css yield straight line with slope: –Km, &
y‐intercept:
Vmax

26. CHRONOPHARMACOKINETICS
• CHRONOPHARMACOKINETICS:
It involves the study of temporal changes in drug
absorption, distribution, metabolism & excretion with
respect to time of administration.
 CHRONOBIOLOGY:
 Science that studies the biological rhythms.
 CHRONOTHERAPEUTICS:
 Application of chrono biological principles to the
treatment of diseases.

27. SCOPE OF CHRONOPHARMACOKINETICS
STUDIES:
 Daily variation in pharmacokinetics.
 Narrow therapeutic range.
 Circadian phase dependent diseases.

28. BODY RHYTHMS
 These are the biological process that show cyclic variation over
time.
 TYPES OF BODY RHYTHMS:
 1. Carcadian rhythms:
Which lasts for about one day like:
 Sleep walking rhythm
 The body temperature

29.  2.Ultradian rhythms:
shorter than a day
Seconds(like heart beat)
 Infradial rhythms:
 Longer than a day
Monthly rhythm-menstrual cycle
Yearly rhythm-bird migration

31. CIRCADIAN DEPENDENCE OF DRUG PHARMACOKINETICS
 ABSORPTION:
 Is altered by circadian changes in
 Gastric emptying time
 Gastrointestinal blood flow
 Gastric acid secretion & pH
 Most liphophilic drugs seems to be absorbed faster when the drug is taken in
the morning compared with the evening.
 Eg: absorption of valproic acid larger in the morning than in the evening.

32.  DISTRIBUTION : Is altered by circadian changes
in
 Body size & composition
 Blood flows in various organs
 Drug protein binding
Peak plasma concentration of plasma proteins like
albumin occurs early in the afternoon, while troughs
are found during the night.
Eg: maximum binding of antineoplastic like cisplatin
to plasma proteins is in afternoon & minimum in the
morning

33.  METABOLISM:
 Is altered by circadian changes in
 Liver enzyme activity
 Hepatic blood flow
For drugs with low extraction ratio depends on liver
enzyme activity.
For drugs with high extraction ratio depends on
hepatic blood flow.

34. • EXCRETION:
• Is altered by circadian changes in
• Glomerular filtration
 Renal blood flow
 Urinary pH
 Tubular reabsorption
• All lower during the resting period than in activity period.
 Eg: Acidic drugs like sodium salicylate excreted quickly after evening
than morning administration.

35. FACTORS EFFECTING CIRCADIAN RHYTHMS
• Food
 Meal timing
 Gastro-intestinal motility
 Digestive Secretions
 Intestinal blood flow
 Light
 The timing of exposure to light
 The length of exposure
 Intensity & wavelength of light

36. DRUGS THAT UNDERGO CHRONOKINETICS:
 Antibiotics - Amino glycosides
Amikacin
 General anaesthetics - Benzodiazepines
Halothane
 NSAIDS - Indomethacin
Ketoprofen
 Anticancer Drugs – 5-Flurouracil
Cisplatin

37. Diseases Circadian Rhythms
Osteoarthritis
Symptoms worse in middle (or) later
of the day
Rheumatoid Arthritis Most intense on awakening
Peptic Ulcers Symptoms worse in the early
(sleep)
Bronchial Asthma Exacerbations more common during
sleep
Allergic rhinitis Worse in early a.m/upon arising

38. Pharmacokinetics and pharmacodynamics in the
elderly
 Age related Physiological Alterations
 Pharmacodynamics
 Cardiovascular Effects
 Effects on central nervous system
 Electrolytes
 Drug-Drug interactions
 Drug-disease interactions
 Drug-food interactions

39. THANK YOU