Renal Excretion of Drugs

1-Glumarular Filtration
2-Tubular Secretion
3-Tubular Reabsorption
RENAL DRUG EXCRETION

 Renal excretion is a major route of elimination for many

drugs.
 Drugs that are eliminated by renal excretion are;
i- Nonvolatile,
ii-Water soluble,
iii- Have a low molecular weight (MW),
iv- Slowly bio transformed by the liver.
 The processes by which a drug is excreted via the kidneys
may include any combination of the following:
1-Glomerular filtration
2- Active tubular secretion
3- Tubular reabsorption
 1-Glomerular filtration

 Glomerular filtration is unidirectional process that occurs

for most small molecules (MW < 500) dissociated (ionized)
drugs.
 Protein-bound drugs behave as large molecules and do not
get filtered at the glomerulus.
 The major driving force is the hydrostatic pressure within
the glomerular capillaries.
GFR-----

 Glomerular filtration rate (GFR) is measured by using a

drug ,eliminated by filtration only
(the drug is neither reabsorbed nor secreted).
E.g.. inulin and creatinine.
 GFR is equal to 125-130 ml/min.
 The value for the GFR correlates fairly well with body
surface area.
GFR--------

 Glomerular filtration of drugs is directly related to the free

or non protein-bound drug concentration in the plasma.
 As the free drug concentration in the plasma increases,
the glomerular filtration for the drug increases
proportionately, thus increasing renal drug clearance for
some drugs.
2-Tubular secretion

  It
is the transfer of materials from peritubular capillaries
to renal tubular lumen, and is the opposite process of
reabsorption.
 This secretion is caused mainly by active transport and
passive diffusion.
 Usually only a few substances are secreted, and are
typically waste products.
 Active tubular secretion

 It is an active transport process.

 It is a carrier-mediated system that requires energy input,
because the drug is transported against a concentration
gradient.
 The carrier system is capacity limited and may be saturated.
 Drugs with similar structures may compete for the same
carrier system.
 For example, probenecid competes with penicillin for the
same carrier system.
 Two active renal secretion systems have been identified, for
(1) weak acids
(2) weak basis
 Active tubular secretion rate is dependent on renal
plasma flow.
 Drugs commonly used to measure active tubular
secretion include p -amino-hippuric acid (PAH) and
iodopyracet (Diodrast).
 These substances are both filtered by the glomeruli and
secreted by the tubular cells.
 Active secretion is extremely rapid for these drugs, and
practically all the drug carried to the kidney is eliminated
in a single pass.
 The clearance for these drugs therefore reflects the
effective renal plasma flow (ERPF), which varies from 425
to 650 mL/min.
Effect of drug protein binding on active
secretion
 For a drug that is excreted solely by glomerular filtration,
the elimination half-life may change markedly in
accordance with the binding affinity of the drug for
plasma proteins.
 Drug protein binding has very little effect on the
elimination half-life of the drug excreted mostly by active
secretion.
 Because drug protein binding is reversible, drug bound to
plasma protein rapidly dissociates as free drug is secreted
by the kidneys.
 For example, some of the penicillins are extensively
protein bound, but their elimination half-lives are short
due to rapid elimination by active secretion.
Mechanisms of Secretion

 The mechanisms by which secretion occurs are similar to

those of reabsorption, but
in the opposite direction.
 Passive Diffusion-
movement of molecules from the peritubular capillaries to
the interstitial fluid within the nephron by concentration
gradient.
 Active transport-
movement of molecules via ATPase pumps, that transport
the substance through the renal epithelial cell into the
lumen of the nephron.
 The substances that are secreted into the tubular fluid for
removal from the body include:
  potassium ions (K+),
 hydrogen ions (H+),
 ammonium ions (NH4+),
 creatinine, urea some hormones, and some drugs (e.g.,
penicillin).
 3-Tubular reabsorption
 The process by which solutes and water are removed from
the tubular fluid and transported into the blood.
 It occurs after the drug is filtered through the glomerulus.
 It can be an active or a passive process.
Mechanisms of Reabsorption

 As the fluid filtered from blood, called filtrate, passes

through the nephron, much of the filtrate and its contents
are reabsorbed into the body.
 Reabsorption is a finely tuned process that is altered in
maintaining homeostasis of blood volume, blood
pressure, plasma osmolarity, and blood pH.
 Reabsorbed fluids, ions, and molecules are returned to
the bloodstream through the peri-tubular capillaries, and
are not excreted as urine.
Mechanisms of Reabsorption cont…..

 The mechanisms of reabsorption into the peri-tubular capillaries

include:
1- Passive Diffusion-
passing through plasma membranes of the kidney epithelial cells by
concentration gradients.
2- Active Transport-
membrane bound ATPase pumps (NA+/K+ ATPase pumps) with carrier
proteins carry substances across the plasma membranes of the kidney
epithelial cells by consuming ATP.
3- Cotransport
this process is particularly important for reabsorption of water.
Water can follow other molecules that are actively
transported, particularly glucose and sodium ions in the
nephron.
4- Through tight junctions
Some substances can also pass through tiny spaces in between
the renal epithelial cells, called tight junctions.
 For completely reabsorbed (eg, glucose),the value of
clearance of the drug is approximately zero.
 For drugs that are partially reabsorbed, clearance values
are less than the GFR of 125-130 ml/min.
Factors affecting reabsorption

1- The pH of the fluid in the renal tubule (ie,urine)

2- The pKa of the drug
effects the reabsorption of drugs that are weak acids or
weak bases.
 Both of these factors determine the percentage of
dissociated and un dissociated drug.
 The undissociated species is more lipid soluble and
greater membrane permeable and is easily reabsorbed.
 The pKa of the drug is a constant, but the normal urinary
pH may vary from 4.5 to 8.0, depending on diet,
pathophysiology, and drug intake.
 Difference between reabsorption and RENAL
SECRETION
RENAL SECRETION REABSORPTION

1- deals with filtering, cleaning of 1- Deals with retaining them

Substances from the blood.
2- occurs throughout the nephron, 2- takes place in distil parts of the
from the proximal convoluted tubules mostly.
tubule to the collecting duct at the
end of the nephron.
RENAL CLEARANCE OF DRUGS

 Renal clearance , ClR , is defined as the volume of plasma

that is cleared of drug per unit time through the kidney.
 Similarly, renal clearance may be defined as a constant
fraction of the VD that is excreted by the kidney per unit
time.
 Renal clearance is defined as the urinary drug excretion
rate (dDu /dt ) divided by the plasma drug concentration
(C p ).
 For any drug cleared through the kidney, the rate of the
drug passing through kidney (via filtration, reabsorption,
and/or active secretion) must equal the rate of drug
excreted in the urine.
 Rate of drug passing through kidney = rate of drug
excreted 
 ClR is renal clearance,
 Cp is plasma drug concentration,
 Qu is the rate of urine flow
 Cu is the urine drug concentration.
As the excretion rate = Qu Cu = dDu /dt
 Renal clearance may be measured as
DETERMINATION OF
RENAL CLEARANCE

1- Graphical Methods
 When the rate of drug excreted in
urine (dDu/dt) is plotted against Cp, the clearance is given
by the slope of the curve obtained .
 For a drug that is excreted rapidly, dDu/dt is large, the
slope is steeper, and clearance is greater (line A).
 For a drug that is excreted slowly through the kidney, the
slope is smaller (line B).
FILTRATION AND ACTIVE SECRETION

 For a drug that is primarily filtered and secreted, with

negligible reabsorption, the overall excretion rate will
exceed GFR .
 At low drug plasma concentrations, active secretion is not
saturated, and the drug is excreted by filtration and active
secretion.
 At high concentrations, the percentage of drug excreted
by active secretion decreases due to saturation.
Excretion rate-versus-plasma level curves for
a drug that demonstrates active tubular secretion and
a drug that is secreted by glomerular filtration only.
 Graph representing the
decline of renal clearance.
 As the drug plasma level
increases to a concentration that saturates the active
tubular secretion, glomerular filtration becomes the major
component for renal clearance.
Model-Independent Methods

 Clearance rates may also be estimated by a single

(nongraphical) calculation from knowledge of the [AUC] ,
the total amount of drug absorbed, FD0 , and the total
amount of drug excreted in the urine, Du .
 For example, if a single IV bolus drug injection is given to a
patient and the [AUC]is obtained from the plasma drug
level-time curve, then total body clearance is estimated
by
 If the total amount of drug excreted in the urine, Du has been
obtained, then renal clearance is calculated by