Transcript Excretion Lecture 1 - Liverpool John Moores University

Drug excretion 1
Contents ...
• Renal excretion
• Creatinine clearance
Excretion
The removal of a drug molecule
from the body without chemical
modification.
Generally in urine, but occasionally
in bile etc.
Kidney
Glomerular Fitration
Rate (GFR)
125ml/min
Plasma flow
650ml/min
Filtration
Urine
1ml/min
Acid Base
Active
secretion
99% of H20 +
Lipid soluble
drugs
Reabsorption
Processes involved in renal excretion: 1
Filtration
• Passive process (Pressure driven)
• 20% of plasma volume is filtered
• Small molecules - Yes
• Large molecules - No
Most proteins not filtered. Drugs which are
extensively protein bound will also not be
filtered.
Processes involved in renal excretion:
Active secretion
• Energy requiring
• Can generate positive concentration
gradients
• Two separate mechanisms for acids &
bases
• Saturable
• Possible interactions
2
Processes involved in renal excretion: 2
Active secretion
ACIDS
Furosemide
Penicillins
Probenecid
BASES
Quinine
Quaternary
ammonium salts
Probenecid and penicillins share same mechanism.
Probenecid competes with penicillins.
Penicillin clearance reduced.
Processes involved in renal excretion: 3
Reabsorption
• 99% of water is reabsorbed
• Lipid soluble drugs reabsorbed along
with the water.
• Only very water soluble molecules can
be efficiently excreted by the kidneys.
Ion trapping
Urine pH varies (4.5 - 8.0). Consider a barbiturate
overdose. Sodium bicarbonate may be given to make
the urine alkaline
Urine
pH 8.0
Rest of body
pH 7.4
Non-ionised
Non-ionised
Ionised
Ionised
Barbiturate moves into urine - eliminated from body.
High renal clearance
If renal clearance is greater than G.F.R.
then there must be active secretion.
Max possible renal clearance is approx.
650 ml/min (All plasma cleared).
e.g. Aminohippuric acid
Low renal clearance
If clearance is much less than
G.F.R. then either:
• Not filtered or
• Extensively reabsorbed
e.g. antipyrine, thiopental
Creatinine clearance
Creatinine is a waste product formed
continuously by muscle.
•Filtered by kidneys
•Almost no active secretion
•Almost no reabsorption
Creatinine clearance
approximately equals
filtration rate (G.F.R.)
Creatinine clearance used as an estimate of G.F.R.
Why are creatinine clearance
and GFR important in ADME?
The clearances of many renally excreted
drugs are closely linked to GFR. e.g. The
clearance of gentamicin approximately equals
GFR and therefore also approximates to
creatinine clearance.
When calculating a dosage regime we can
assume that gentamicin clearance will equal
creatinine clearance
Factors influencing serum
creatinine concentration
1) Creatinine production rate depends upon
muscle mass, which in turn depends upon:
• Body weight
• Age (% muscle declines with age)
• Sex (Men have higher % muscle than women)
2) Creatinine clearance rate
Cockcroft & Gault
Cockcroft & Gault took a series of individuals and
measured their serum creatinine concentrations, ages,
weights and creatinine clearances and found the following
relationships:
SrCr = 1.23 x (140 – Age) x Wt ……….…. in men
CrCl
SrCr = 1.04 x (140 – Age) x Wt …………. in women
CrCl
These can then be re-arranged to produce equations that
estimate creatinine clearance.
Estimating creatinine
clearance
Cockcroft & Gault equation
Men: CrCl = 1.23 x (140 – Age) x Wt
SrCr
Women: CrCl = 1.04 x (140 – Age) x Wt
SrCr
CrCl = Creatinine clearance (ml/min)
Age (Years)
Wt = Weight (kg)
SrCr = Serum creatinine (μmol/l)
Cockcroft & Gault equation
Applicability:
There are some situations where the equation is not
applicable (e.g. children and in pregnancy.)
There may also be an over-estimate of creatinine
clearance in obese subjects, because large amounts of fat
are included in the body weight, but this does not produce
creatinine. “Ideal” body weight (based on height and
build) will produce a better estimate.
Case
A woman, 30 years of age, weighing 70Kg, with a
serum creatinine of 71 μmol/l .
Will receive 100mg gentamicin 3 times daily (i.v.)
Target peak concs are 4-8 mg/L
trough concs < 2mg/L
• Predict Css,max and Css,min.
• Will regime be satisfactory?
Outline approach
• Estimate creatinine clearance (and assume
gentamicin clearance to be the same)
• Predict V from population data
• Predict K from clearance and V
• Predict Css,max and Css,min
• Compare against desirable concentrations.
Estimate creatinine
clearance
For women: CrCl = 1.04 x (140 – Age) x Wt
SrCr
CrCl = 1.04 x (140 – 30) x 70
71
= 113 ml/min
= 6.8 L/h
Now assume that gentamicin clearance will
also be 6.8 L/h
Predict V and K
V = 0.25 L/Kg x 70 Kg
= 17.5 Litres
Cl = K.V
K = Cl / V
= 6.8 L/h
17.5 L
= 0.389 h-1
Predict Css,max & Css,min
Css,max = D/V . 1/(1-e-Kt)
= 100mg/17.5L . 1/(1-e-0.389h-1 x 8h)
= 5.71mg/L . 1/(1 - e-3.112)
= 5.71mg/L . 1/(1 - 0.0445)
= 5.71mg/L . 1/0.956
= 5.97 mg/L
Css,min = Css,max - D/V
= 5.97 - 5.71 mg/L
= 0.26 mg/L
Compare to desirable
concentrations
Desirable
Predicted
OK?
--------------------------------------------------------Css,max 4-8 mg/L
5.97 mg/L

Css,min
<2 mg/L
0.26 mg/L

The regime should be satisfactory
Terms with which you
should be familiar ...
• Filtration
• Active secretion
• Reabsorption
• Glomerular Filtration Rate (GFR)
• Creatinine clearance
What you should be
able to do
 Describe
the various processes by which drugs
may be added to or removed from urine.
 Describe how adjustment of urinary pH may be
used to enhance drug excretion in cases of
overdose.
 Estimate creatinine clearance from serum
creatinine concentration, body weight, age and
gender.