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Ô It is the irreversible removal of the drug from the body by
all routes of elimination.
Ô Usually divided into two components :
i. Excretion
ii. Biotransformation
Ô Drug elimination in the body involves many complex rate
processes,
Ô Elimination processes may vary in each organ which is
eliminating drug.
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Ô It is the removal of the intact drug.
Ô Drugs are mainly excreted by renal excretion.
Ô Other pathways : Excretion of drug in to bile, sweat,
milk ( via lactation ), lungs, or other body fluids.
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Ô It is the process of drug elimination from the body
or from a single organ without identifying the
individual processes involved.
Ô It may also be defined as ;
͞ the volume of fluid cleared of drug from the
body per unit of time.͟
Ô Units : mL/min or L/hr or unit/min

 

Ô 

 

 

Ô Y
IOLOG
:
£ One of the major eliminating organ of the body,
and so as for the drugs.
£ Two major endocrine functions it performs;
Ô ecretion of renin
Ô ecretion of erythropoietin

 


 

Ô BLOOD UYYL
:
£ The kidneys represent about 0.5% of the total body
weight and receive approximately 20ʹ25% of the cardiac
output.
Ô Renal Blood Flow:
£ 
 (RBF) is the volume of blood flowing
through the renal vasculature per unit time. Renal blood
flow exceeds 1.2 L/min or 1700 L/day.
Ô Renal Ylasma Flow:
£ m

 (RYF) is the renal blood flow minus
the volume of red blood cells present.

 

Ô RELATION IY BETWEEN RYF AND RBF:

Ô Assuming a hematocrit of 0.45 and a RBF of 1.2 L/min, using

the above equation,
RYF = 1.2 ʹ (1.2 x 0.45) = 0.66 L/min or 660 mL/min
£ approximately 950 L/day.

 

Ô GLOMERULAR FILTRATION RATE:
£ ͞The volume of water filtered out of the plasma through
glomerular capillary walls into Bowman's capsules per
unit of time.͟
Ô Normal value:
£ The glomerular filtration rate (GFR) is about 125 mL/min
in an average adult, or about 20% of the RYF.
Ô The ratio GFR/RYF is the filtration fraction.

 

Ô REGULATION OF RENAL BLOOD FLOW:
Ô Basic determinants ʹ
£ Renal arterial pressure
£ Glomerular capillary hydrostatic pressure

 

Ô GLOMERUAL FILTRATION AND URINE FORMATION:
Ô A normal adult male subject has a GFR of
approximately 125 mL/min.
Ô About 180 L of fluid per day are filtered through the
kidneys.
Ô In spite of this large filtration volume, the average
urine volume is 1ʹ1.5 L.

 

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Ô Elimination can occur by one or more pathways.
Ô Rate of overall elimination process is governed by
elimination rate constant ͚k͛.
Ô If a drug is excreted by renal excretion, metabolism
and biliary excretion, overall elimination rate
constant k will be equal to,
£ k = ke + km + kb

Ô Multiplying both the sides by Vd,

£ kVd = keVd + kmVd + kbVd OR
£ Total Body Clearance = Renal Clearance + Metabolic clearance +
Biliary clearance
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Ô It is major route of elimination for many drugs.
Ô Three major processes :
1. Glomerular Filtration
2. Active Tubular ecretion
3. Tubular Reabsorption
 
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Ô GLOMERULAR FILTRATION:
£ Uni-directional process for molecules less than weight of
500.
£ Molecules include un-dissociated (non-ionized) and
dissociated (ionized).
£ Yrotein-bound drugs do not get filtered.
£ Major driving force is the hydrostatic pressure.
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Ô GFR is measured by using a drug that is eliminated
by filtration only (i.e., the drug is neither
reabsorbed nor secreted).
Ô Examples:
Ô Inulin
Ô Creatinine
Ô o, clearance of inulin would be equal to the
normal GFR i.e. 125-130 mL/min.
Ô GFR is directly proportional to concentration of free
drug in plasma.

 
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Ô It is an active transport process, meaning requires energy.
Ô This system is capacity limited and may be saturated.
Ô Two active systems have been identified, systems for;
£ Weak acids
Ô e.g, Yrobenecid and Yenicillins
£ Weak bases
Ô e.g, Ondansetron hydrochloride
Ô Drugs commonly used to measure active tubular secretion
include
-amino-hippuric acid (YA ) and iodopyracet
(Diodrast).

 
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Ô The elimination half life of drugs, actively secreted
by the kidney, is small.
Ô Example:
Ô Yenicillins are extensively protein bound, but their elimination
half-lives are short due to rapid elimination by active secretion.

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Ô    

occurs after the drug is
filtered through the glomerulus and can be an
active or a passive process.
Ô Drug may be completely reabsorbed, e.g. Glucose;
clearance value for such component would be zero.
Ô If partially reabsorbed, then value is always less
than normal GFR i.e., 125ʹ130 mL/min.

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Ô It is influenced by the p of the urine and the pka value of
the drug.
Ô These factors render the drug to be in dissociated or un-
dissociated form.
Ô Un-dissociated drugs are easily reabsorbed.
Ô Normal urinary p may vary from 4.5 to 8.0.
Ô Drugs can decrease (acidify) e.g.,ascorbic acid or increase (
alkalanize ) e.g., odium carbonate the p of the urine.
Ô Most important changes in urinary p are caused by fluids
administered intravenously
£ e.g. olutions of bicarbonate or ammonium chloride.

mm  m



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Ô The percentage of ionized weak acid and basic drug
can be obtained from the endersonʹ esselbalch
equation.
Ô For acidic :

Ô For basic :
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Ô Renal excretion rate for any drug can be calculated as

follows;
£ Renal excretion rate = Rate of filtration + Rate of active
secretion ʹ Rate of reabsorption
Ô Example :
£ Find Renal excretion rate for Yenicillins when,
Ô Rate of filtration = 120 mg/min
Ô Rate of active secretion = 1080 mg/min
£ From formula,
Ô Rate of excretion = Rate of filtration + Rate of active secretion
Ô Rate of excretion = 120 + 1080
= 1200 mg/min

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Ô As renal excretion rate of most drugs follows first-

order kinetics, the renal excretion rate at any time
is equal to;

Ô Where,
£ Ae is the amount of the drug excreted in urine
£ ke is the first-order renal excretion rate constant
£ A is the amount of the drug in the body.

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Ô But as urine samples are usually collected over

certain time intervals, so;

Ô Where,
£ ȴAe is the amount of the drug excreted in urine over a
certain urine collection interval ȴt
£ ȴAe/ȴt is the renal excretion rate
£ ke is the first-order renal excretion rate constant
£ Aaverage is the average amount of the drug in the body
during the urine collection interval
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Ô elect the length of time for each of the urine collection

intervals
Ô Collect urine samples at the end of each urine collection
interval
Ô Measure the volume of each urine sample
Ô Determine the drug concentration in each urine sample
Ô Calculate the amount of the drug excreted during each urine
collection interval as;
£ Amount excreted = Drug conc. in urine X ample volume
Ô Calculate the renal excretion rate as,
£ Renal excretion rate = Amount excreted / Time of urine collection
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Ô Renal excretion rate after a single IV dose can be
described by

Ô Where,
£ ke is the renal excretion rate constant
£ Ao is the initial amount of the drug in the body
£ k is the overall elimination rate constant
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m

 m
Ô Ylotting the renal excretion rate versus time on semilog graph paper will
give us a straight line, and also we can calculate half-life and renal
excretion rate constant of the drug.
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Ô It defined as,
͞ the volume of the blood or plasma that is completely
cleared of the drug per unit time by the kidney͟
Ô Renal excretion rate is determined by,

Ô Where,
£ At-mid is the amount of the drug in the body at the
midpoint of the urine collection interval i.e.,
approximately equal to the average amount of the drug
during the urine collection interval.
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Ô Now, as the amount of drug is equal to the drug
concentration times the volume of distribution, so
the previous equation becomes,

£ Cpt-mid is the drug plasma conc. at the midpoint of the

urine collection interval
Ô And,

£ Because ke X Vd = Renal clearance

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Ô Ylotting renal excretion rate versus the plasma
conc. at the middle of the urine collection interval
would give a straight line on the graph paper, and
slope of the line is equal to the renal clearance.
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Ô  !"##$!%&%!!&#$'()*"
&#+ !"*#,"-m
£ Drugs with renal clearance  than the GFR are
actively secreted in the renal tubules.
£ Drugs with renal clearance  than the GFR are most
probably filtered and then reabsorbed OR drugs
undergo filtration, tubular secretion and then are
reabsorbed.
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Ô Renal clearance of creatinine represents an accurate
measure of the GFR. It is determined as,
£ Collect all the urine excreted over a period of 24 hr
£ Obtain plasma sample and determine plasma creatinine
concentration
£ Determine the total volume of the urine collected and the creatinine
concentration in the urine sample
£ Calculate the total amount of creatinine excreted by,
Ô Amount = Volume of urine X Concentration of creatinine
£ Calculate the creatinine excretion rate by,
Ô Creatinine excretion rate = Amount excreted / Time of urine collection
£ Calculate the creatinine clearance by,
Ô Creatinine clearance= Creatinine excretion rate/Creatinine plasma conc.

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Ô Example-
£ Yatient is asked to collect urine over a 24h hr period
£ Total volume of urine collected = 2200mL
£ Creatinine conc. in urine was found to be 0.2 mg/mL
£ Creatinine conc. in the serum was 3.0 mg/100mL
Ô We want to calculate the creatinine clearance of this patient.

Cont͛d͙

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Ô Total amount of creatinine excreted in 24 hrs,
£ Urine volume X Urine concentration

£ 2200 mL X 0.2 mg/mL = 440 mg

Ô Creatinine excretion rate is calculated as follows,

£ 440 mg / 24 hr x 60 min/hr = 0.3055 mg/min

Ô o creatinine clearance would be,

£ Creatinine excretion rate /erum creatinine concentration i.e.,

£ 0.3055 mg/min / 3 mg/100 mL

£ = 10.2 mL/min


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Ô Estimation of GFR
Ô Estimation of renal plasma flow
Ô Measurement of filtration fraction
Ô Estimation of kidney function

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 m

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Ô Elimination rate constant and half-life (k and t1/2)
Ô Renal excretion rate constant ke
Ô Volume of distribution Vd
Ô Renal clearance CLR
Ô Fraction of dose excreted unchanged in urine
Ô Bioavailability
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