clinical pharmaco kinetics 1 bioavailability, 1st pass, renal clearance 2011
TRANSCRIPT
Clinical Pharmacokinetics-1
Prof. Dr. Talat Ahmed
THEORIES OF DRUG DISTRIBUTION AND ELIMINATION
THEORIES OF DRUG DISTRIBUTION AND ELIMINATION
1. Single compartment theory.
2. Two compartment theory
3. Multiple compartment theory.
F, AUC, CL, Vd, t1\2, Css
a)
central
b) peripheral
blood
CSF
lung
liver
Kidney
muscle
skin
fat
bones
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 I\M 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 absorption1)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/Generic1. Same active ingredient2. Same strength /concentration3. Same Dosage Form4. Same route of Admn.
BioequivalentWhen rate & extent of bioavailability of active ingredient
in two products is similar.Therapeutic EquivalenceWhen 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
OralTopical
TransdermalIntramuscular
Subcutaneous
SublingualRectal
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 – CO
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 clearanceCLorgan = Rate of eliminationORGAN
CP
Total systemic clearance:
CLsyst = CLrenal + CLliver + CLother
CLorgan = Blood flow x Extraction Ratio
= Q x ER
= Q x Ci – CO
Ci
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 EliminationZero 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/minRenal clearance = 480 ml/min
Estimation of GFRThe most commonly used formula is the "4-variable MDRD," (Modification of Diet in RenalDisease Study Group) which estimates GFR using
Four variables: serum creatinine, age, race, and gender
Cockcroft-Gault formula There is age related decline in renal
functionsThere is decline of muscle mass with ageTherefore reduction in production of
creatinineCreatinine clearance (mL/min)=
140-age x wt in kg 72 x serum creatinine in mg/dL
(x 0.85 for females)
Thank You