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

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