1. Clinical Pharmacokinetics-1
Prof. Dr. Talat Ahmed

2. THEORIES OF DRUG DISTRIBUTION AND
ELIMINATION

3. THEORIES OF DRUG DISTRIBUTION
AND ELIMINATION
1. Single compartment a) b)
theory. central peripheral
2. Two compartment blood muscle
theory
CSF skin
3. Multiple
lung fat
compartment
liver bones
theory.
Kidney
F, AUC, CL, Vd, t12, Css

4. BIOAVAILABILITY

5. Bioavailability (F) is the fraction of
unchanged drug reaching the systemic
circulation.
I/V administration = 1F (100% bioavailability)
 AUC= area under curve:
It is a measure of the extent of bioavailability
given by a particular route.
 F= AUC after IM or oral dose
AUC after I/V dose

6. F= AUCoral/AUC i/v

7. FACTORS AFFECYING
BIOAVAILABILITY
1. EXTENT OF ABSORPTION (= f)
2. RATE OF ABSORPTION
3. FIRST PASS ELIMINATION

8. Factors Affecting Bioavailability
1. EXTENT OF ABSORPTION (= f) :
Bioavailability is the function of absorption=f
digoxin, 70% intestinal microflora
atenolol, 56% too hydrophilic
acyclovir 23% too lipophilic
Grape fruit juice:↑ drug absorption
1)P-glycoprotein inhibition 2)↓wall metabolism

9. 2. RATE OF ABSORPTION:
it affects rate of availability,
determined by:
a) Drug formulation
b) Amount of given drug.
c) Site of Administration.

10. a) Drug formulation

11. a) Drug formulation
• Disintegration & dissolution time Depends:
1.Compression pressure
2.Moisture Content
3.Nature of additives: excipients - starch,
lubricants, disintegrents
4.Particle size
5.Polymorphism of molecule or ions
6.pH

12. Bioequivalence
Pharmaceutical Equivalent/Generic
1. Same active ingredient
2. Same strength /concentration
3. Same Dosage Form
4. Same route of Admn.
Bioequivalent
When rate & extent of bioavailability of active ingredient
in two products is similar.
Therapeutic Equivalence
When two products produce same response in same
dosage (e.g. aconitine hazard)

13. b) Amount of given drug
• FIRST ORDER ABSORPTION:
rate of absorption is proportional to the amount
of drug in gut.
• ZERO ORDER ABSORPTION:
when rate of absorption is not proportionate to
the amount of drug in the gut.
(when full dose is not absorbed from GI fluids)

14. c)Site of Administration
Oral
Topical
Transdermal
Intramuscular
Subcutaneous
Sublingual
Rectal
Inhalation

15. 3. FIRST PASS ELIMINATION:
orally administered drug
↓
gut wall
↓
portal blood
↓
liver
bile systemic circulation

16. The First Pass Effect and
Extraction Ratio
Effect of first pass elimination on
bioavailability is expressed as
extraction ratio = ER
If a drug is completely absorbed from the gut
its systemic bioavailability
F = l (100 %)
If it passes through liver, it will be decreased
by hepatic extraction
F = l – ER

17. Extent Of Absorption = f
(predicts systemic bioavailability of drug)
F = f x (1- ER)
For morphine f =1
ER = 0.67
F = 1 x (1- 0.67) = 33%
( observed value 24%)

18. Highly Extracted Drugs
Therapeutic blood concentration can be
reached by high oral dose
Lidocaine 20 %
Verapamil 20%
Propranolol 26%
Lidocaine P.O →↑metabolites
↓
CNS toxicity

19. Poorly Extracted Drug
Diazepam 100%
Digitoxin 90%
Theophylline 96%
Shunting of blood past the liver will cause little
change in availability.
ER = Clliver
Q
Clliver = Q x Ci – C O
Ci

20. Drug clearance

21. Clearance (CL) is the measure of
removal of drug from body
• expressed as:
volume of plasma from which all drug
is removed in a given time e.g.
ml/min or L/h
• It is estimated as:
Blood Clearance (CLb),
Plasma Clearance (CLP),
Unbound drug Clearance (CLu)

22. Drug clearance
It is similar to creatinine/urea clearance.
Creatinine Clereance = UV
P
Renal Clearance=
Conc. in urine x rate of urine formation
Conc. in plasma
Clearance of a drug =
Rate of elimination of all routes
Conc. in any body fluid
or CL = Rate of elimination or Dose
C AUC

23. Organ clearance
CLorgan = Rate of eliminationORGAN
CP
Total systemic clearance:
CLsyst = CLrenal + CLliver + CLother
CLorgan = Blood flow x Extraction Ratio
= Q x ER
= Q x Ci – CO
C

24. DRUG CLEARANCE

25. Factors related to clearance
A. First Order Elimination
B. Capacity Limited Elimination
C. Flow Dependent
D. Plasma Protein binding

26. A. First Order Elimination
Rate of elimination = Cp x CL organ
For most drugs elimination is not saturable &
is directly proportional to concentration
Can be calculated by AUC
CL: Dose
AUC

27. CL= Dose/AUC

28. B. Capacity Limited Elimination
Zero Order Elimination, Saturable, Nonlinear,
Dose dependent or Michaelis’ Menten Elimination
Vmax x C
Rate of Elimination= --------------
Km + C
The concentration will keep on rising as
long as dosing continues & steady state
can not be reached.
Ethanol, Phenytoin & Aspirin
AUC can not be used to calculate clearance

29. C. Flow Dependent
Elimination depends on the rate of delivery
of drug to the organ of elimination
CLorgan = Blood flow x Extraction Ratio
= Q x ER
= Q x Ci – CO
Ci

30. D. Plasma Protien binding
& Blood Cell partitioning
• Plasma Protein binding may be important for
extensively bound drugs:
Phenytoin 89%,
Salicylic acid 85% (Aspirin 49%)
 When the amount of unbound drug in plasma
increases the rate of elimination will increase.
 When plasma proteins are lower than normal
then total drug concentration will be lower but
unbound concentration will not be affected.

31. Factors affecting protein binding
• Albumen Concentration In many diseases
albumin level is low, resulting in lower total
drug concentration (phenytoin, salicylate &
disopyramide)
• Alpha1-acid glycoprotein concentration It is
↑ed in acute inflammatory disease ↑ing
total plasma conc. of propranolol, lidocain
& quinidine.
• Capacity limited protein binding
salicylates & prednisolone

32. Renal clearance of
Benzyl Penicillin
Filtration 10 %
Tubular secretion 90 %
Glomerular filtration rate = 127ml/min
Renal clearance = 480 ml/min
Estimation of GFR
The most commonly used formula is the
"4-variable MDRD," (Modification of Diet in Renal
Disease Study Group) which estimates GFR using
Four variables: serum creatinine, age, race, and
gender

33. Cockcroft-Gault formula
 There is age related decline in renal
functions
 There is decline of muscle mass with age
 Therefore reduction in production of
creatinine
Creatinine clearance (mL/min)=
140-age x wt in kg
72 x serum creatinine in mg/dL
(x 0.85 for females)

34. Thank You