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Clinical Pharmacokinetics-1



     Prof. Dr. Talat Ahmed
THEORIES OF DRUG DISTRIBUTION AND
           ELIMINATION
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
BIOAVAILABILITY
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
F= AUCoral/AUC i/v
FACTORS AFFECYING
       BIOAVAILABILITY

1. EXTENT OF ABSORPTION (= f)
2. RATE OF ABSORPTION
3. FIRST PASS ELIMINATION
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
2. RATE OF ABSORPTION:
   it affects rate of availability,
     determined by:

a) Drug formulation
b) Amount of given drug.
c) Site of Administration.
a) Drug formulation
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
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)
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)
c)Site of Administration
           Oral
           Topical
        Transdermal
       Intramuscular
      Subcutaneous
        Sublingual
           Rectal
         Inhalation
3. FIRST PASS ELIMINATION:
         orally administered drug
                    ↓
               gut wall
                    ↓
               portal blood
                    ↓
                    liver

            bile       systemic circulation
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
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%)
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
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
Drug clearance
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)
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
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
DRUG CLEARANCE
Factors related to clearance
A.   First Order Elimination
B.   Capacity Limited Elimination
C.   Flow Dependent
D.   Plasma Protein binding
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
CL= Dose/AUC
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
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
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.
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
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
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)
Thank You

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Clinical pharmaco kinetics 1 bioavailability, 1st pass, renal clearance 2011

  • 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
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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)