BIOPHARMACEUTICS AND

PHARMACOKINETICS
613-T

MISS NIMRA WAHEED

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 LEARNING OBJECTIVES
• MECHANISMS OF RENAL EXCRETION
1. glomerular filtration
2. tubular secretion
3. reabsorption.
 PREVIOUS LECTURE
• we have studied othe 3 routes of elimination
• we have kidney function test

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MECHANISMS OF RENAL EXCRETION
There are two mechanisms by which a drug is passed from blood into the
glomerular filtrate:
1. filtration through glomeruli (glomerular filtration) and
2. active secretion into kidney tubule (tubular secretion).
3. A third process which has significant influence on overall drug removal is
reabsorption.
Drugs may pass from glomerular filtrate into blood by active and passive
reabsorption (tubular reabsorption). The net effect of these processes is that a
constant fraction of drug present in renal arterial blood is removed and appears
in urine.

GLOMERULAR FILTRATION
The kidneys represent about 0.5% of the total body weight and receive a large
blood supply via the renal artery. The blood supply received by the kidneys is
approximately 20% to 25% of the cardiac output. It is not surprising .that the
kidneys have a very rich blood supply since they continuously cleanse the blood
and adjust its composition.
GLOMERULAR FILTRATION RATE

Blood is constantly circulated through the kidneys at the rate of about 1,700
L/day. The rate of plasma flow through the kidneys is about 850 L to 1,000 L
per day and about 20% of this volume is filtered. Therefore, the amount of
fluid filtered from the blood into the glomerular capsule each minute is:
GFR 20% of (850 L/day to 1000 L/day) = 170 to 200 L/day
GFR = 7 to 8 L/hour = 118 to 140 mL/min.
The amount of fluid filtered from blood into glomerular capsule per unit
time is known as glomerular filtration rate (GFR). A glomerular filtration rate
of 130 mL/min is considered normal in healthy state, although 131 ± 22
mL/min is the normal range. The blood in the kidney passes through many
subunits known as glomeruli, which serve as filters.
Molecules which are small in size (low molecular weight) and spherical in
shape are filtered easily and long-chain molecules and/or high molecular
weight compounds are not freely filtered. The glomerular capillaries filter
plasma in such a way that any molecule can pass through the capillaries
irrespective of its charge, provided its molecular weight is under about
20,000. When the molecular weight exceeds 20,000, the shape of the
molecule then becomes the determining factor for filtration. For example,
globular hemoglobin molecule (molecular weight = 64,500) readily filters
through glomerular capillary wall but serum albumin (molecular weight =
68,000), which an elongated molecule, either filters much less readily or is
almost completely held back.
The upper -limit of filterable molecular weight appears to be in the
vicinity of about 50,000. This explains why the filtrate in normal kidney.is
practically free of proteins having a molecular weight of 70,000 or more.
So far as drugs are concerned, with the exception of a few
macromolecular substances, e.g., dextrans and heparin, all drugs pass the
glomerulus as readily as water.
FACTORS INFLUENCING GLOMERULAR FILTRATION

The factors influencing glomerular filtration are those factors which govern the
rate of filtration at the capillary beds. These are
1. total surface area available for filtration,
2. permeability of the filtration membrane, and
3. net filtration pressure.
The first two factors (total surface area available for filtration and permeability of
the filtration membrane) do not pose a problem as far as glomerular filtration is
concerned. This is because the glomerular capillaries are exceptionally permeable
and have a huge surface area available for filtration. Therefore, glomerular
filtration rate is essentially directly proportional to the net filtration pressure. The
net filtration pressure is the glomerular hydrostatic pressure minus the sum of
glomerular osmotic pressure and capsular hydrostatic pressure. Under normal
conditions, the glomerular hydrostatic pressure is about 55 mm of mercury, the
glomerular osmotic pressure is about 30 mm of mercury, and the capsular
hydrostatic pressure is about 15 mm of mercury. Therefore, the net filtration
pressure is: 55 mm ofmercury - 30 mm ofmercury - 15 mm ofmercury = 10 mm of
mercury
On the other hand, a drop in glomerular pressure of only about 15 % (which is
less than 1 mm of mercury) stops filtration altogether. In other words, a change
in the net filtration pressure can change the rate of glomerular filtration
significantly. Therefore, an increase in the arterial blood pressure in the kidneys
will cause an increase in the glomerular blood pressure which will result in an
increase in the glomerular filtration rate. On the other hand, dehydration, which
causes an increase in the glomerular osmotic pressure, will inhibit formation of
the filtrate.

DETERMINATION OF GLOMERULAR FILTRATION RATE

Glomerular filtration rate can be determined by measuring the extent of

excretion and the plasma level of a test substance. The substance used to
measure filtration rate should -have the following properties.
1. It should be removed from plasma by glomerular filtration.
2. It should not be (actively) secreted or reabsorbed by the tubules.
3. It should not be metabolized, stored, or protein-bound.
4. It should not affect the filtration rate.
Substances commonly used to measure glomerular filtration rate in humans
include mannitol, sodium thiosulfate, and inulin (a polymeric carbohydrate).
Exogenous administration of creatinine is used to measure glomerular filtration
rate in dogs.
TUBULAR SECRETION

The second mechanism by which a drug is passed from blood into the
glomerular filtrate is tubular secretion. Tubular secretion is an active transport
process whereby the drug may is able to be transported against a
concentration gradient from the blood capillaries across the tubular
membrane into the renal tubule. This active process accounts for the fact that
certain drugs, although extensively bound to plasma protein, are rapidly
eliminated from the body essentially by renal excretion; The kidney appears to
be capable of dissociating the drug-protein complex. The penicillins are an
example of drugs that are rapidly eliminated by renal excretion because the
kidney dissociates the drug-protein complex. Two active renal secretion
systems have been identified one for weak acids and another for weak bases.

Tubular secretion is important for a variety of functions, for example:

(a) to dispose substances not already in the filtrate, e.g., penicillin and
phenobarbital.
(b) to eliminate undesirable substances that have been reabsorbed by passive
diffusion, e.g., urea and uric acid.
(c) to control blood pH. When the pH of blood begins to drop, the renal tubule cells
actively secrete hydrogen ions into the filtrate and retain more bicarbonate and
potassium ions. As a result, the pH of blood rises and urine drains off the excess acid.
(d) to remove excessive potassium ions from the body. Nearly all potassium ions in
urine are derived from active tubular secretion because virtually all potassium ions
present in the filtrate are reabsorbed in the proximal convoluted tubule.
The  principle of competition has  been employed  to  provide  a  longer  biological 
half­life of some  drugs.  For  example,  ordinarily,  the  piological  half­life  of penicillin 
is  very  short  because  penicillin  is  eliminated very rapidly.  Probenecid  is 
a weak organic acid which competitively inhibits  tubular secretion  of benzyl 
penicillin,  thereby  decreasing  elimination of penicillin.  Probenecid  has  been used 
clinically  to  increase  biological  half­life  and  therefore  the  duration  of effect 
of penicillin.  The  increased  duration of  effect  prolongs  therapeutic  concentration 
of penicillin  in  plasma,  and  this  strategy  has  been  found  very  useful  in  the 
treatment  of infections,  such  as  meningitis.  Similarly,  small  quantities  of salicylic 
acid  competitively  inhibit excretion of uric  acid  when  the  concentration of uric 
acid  in  urine  is  high (e.g.,  in  gout). 
Examples  of other  commonly  used  drugs  which  are  eliminated  by  tubular 
secretion  include  the  following: 

Acids (Anions)  amino­acids,  acetazolamide,  p­aminohippuric  acid  (PAH),  benzyl 

penicillin,  chlorothiazide,  furosemide, 
indomethacin, penicillin, phenylbutazone, probenecid, salicylic acid,  and thiazide. 

Bases (cations)  cholines,  dopamine,  histamine,  N­methylnicotinarnide,  dibydro­

morpbine,  quinine,  quaternary  ammonium compounds,  and tolazoline.

DETERMINATION OF SECRETION RATE 
Active  tubular  secretion  rate  of  the  drug  is  dependant  on  renal  plasma  flow. 
Therefore,  any  substance  that is  actively secreted by the renal  tubules  can be 
used to  estimate tubular secretion rate,  as  long  as  it  is  not  metabolized, 
stored,  or protein­bound,  and  it does  not  affect  the  tubular secretion rate. 
Drugs  commonly  usedto  measure  active  tubular  secretion  include  p­
arninohippuric  acid  (PAH)  and iodopyracet (diodrast).  These substances 
are not only filtered  through the glomerulus but also vigorously 
secreted in the kidney tubules.  The removal of p­aminohippuric acid from 
arterial blood is  90%  complete  in a single passage through the kidney.
TUBULAR REABSORPTION 

Tubular reabsorption may be considered as a reclamation process that begins as soon 
as the filtrate  enters  the  proximal  tubules.  Because  the  total  blood  volume 
filtersinto  the  renal  tubules  approximately  every 45 minutes, 
all of the plasma would be drained away as urine within an hour were it not for the fac
t 
that most of the tubule contents are quickly reabsorbed (reclaimed) and returned to t
he blood. The filtered  plasma passes through the glomeruli into the renal tubule. 
For  example,  although the glomeruli filter  about 7 to 
8 L of plasma per hour, the amount of urine formed per  hour  is  only  about  60  mL, 
which  represents  less  than 1% of the  volume  of plasma,  filtered  by  the  glomeruli. 
The  balance  of  the  filtered  water  is  reabsorbed.  Similarly,  glucose 
(whichis  a  normal component of plasma) is rarely found in the urine of
healthy individuals because of its quantitative reabsorption into the tubule.
Examples of substances actively reabsorbed from the renal tubule include
glucose, various amino acids, lactate, vitamins, and most ions.
The mechanism of drug transport from the renal tubule appears to be very
similar to passive diffusion of drugs through the gastrointestinal barrier, i.e.,
the tubule membrane is permeable only to lipid-soluble, non-ionized form of
the drug. Consequently, compounds that are charged or possess poor lipid
solubility are poorly reabsorbed. Accordingly, tubular reabsorption of drugs
that are weak organic acids or weak organic bases is dependent on the pH of
the fluids in the renal tubule.
SUMMARY
we have studied mechanisms of renal excretion i.e.
glomerular filtration
tubular secretion
reabsorption.
FURTHER READING AND REFERENCES

• Book: Biopharmaceutics and pharmacokinetics by PL Madan

Chapter 6

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