Drug Clearance

Dr. Abeer Tariq

 “Drug elimination refers to
the irreversible removal of
drug from the body by all
routes of elimination.”
Drug The declining plasma drug concentration
Elimination observed after systemic drug absorption shows
• that the drug is being eliminated from the body
• does not necessarily differentiate between distribution and
elimination
• does not indicate which elimination processes are involved
Drug elimination is usually divided into two major
components:

Excretion and

Biotransformation
 Drug excretion
• is the removal of the intact drug.
• Nonvolatile and polar drugs are excreted mainly by renal
excretion
• Other pathways for drug excretion may include the
excretion of drug into bile, sweat, saliva, milk (via
lactation), or other body fluids.

Excretion and • Volatile drugs, such as gaseous anesthetics, alcohol, or

drugs with high volatility, are excreted via the lungs into

Biotransformati
expired air.

Biotransformation or drug metabolism

on • is the process by which the drug is chemically converted

in the body to a metabolite.
• Biotransformation is usually an enzymatic process. A few
drugs may also be changed chemically by a nonenzymatic
process.
• The enzymes involved in the biotransformation of drugs
are located mainly in the liver.
• Other tissues such as kidney, lung, small intestine, and
skin also contain biotransformation enzymes.
 Clearance

“The term clearance describes the process of drug

elimination from the body or from a single organ
without identifying the individual processes involved”
The units for clearance
The volume concept is
Clearance may be defined are sometimes in
simple and convenient,
as the volume of fluid milliliters per minute
because all drugs are
removed of the drug from (mL/min) but most often
dissolved and distributed
the body per unit of time. reported in liters per hour
in the fluids of the body.
(L/h).
Clearance

Drug clearance is defined as the

“fixed volume of fluid (containing the drug) removed from the drug
per unit of time. The units for clearance are volume/ time (eg,
mL/min, L/h). “
• For example, if the Cl of penicillin is 15 mL/min in a patient and penicillin has a VD
of 12 L, then from the clearance definition, 15 mL of the 12 L will be removed
from the drug per minute.
Clearance

• Alternatively, Cl may be defined as the

“rate of drug elimination divided by the plasma drug concentration.”

• This definition expresses drug elimination in terms of the volume of plasma

eliminated of drug per unit time. This definition is a practical way to calculate
clearance based on plasma drug concentration data.
Equations
Clearance

Clearance is even more important clinically than a half-life for

several reasons.
Clearance---------relates to the systemic exposure of a
drug-----------useful PK parameter clinically ---------calculate doses
to administer.

Clearance ---------drug elimination regardless of their mechanism.

 CLEARANCE MODELS
The calculation of clearance from a rate constant and a volume of distribution assumes a defined
compartmental model,

whereas clearance estimated directly from the plasma drug concentration-time curve using
noncompartmental PK approaches does not need one to specify the number of compartments that
would describe the shape of the concentration-time curve.

Although clearance may be regarded as the product of a rate constant k and a volume of distribution
V,
CLEARANC
E MODELS
• Physiologic/Organ Clearance
• Noncompartmental Methods
• Compartmental Methods
 Clearance may be calculated for any
organ involved in the irreversible
removal of drug from the body.

Physiologic/ Many organs in the body have the

capacity for drug elimination, including
Organ Clearance drug excretion and biotransformation.

The kidneys and liver are the most

common organs involved in excretion
and metabolism, respectively.
• For any organ, clearance may be defined as the fraction of blood volume containing drug that
flows through the organ and is eliminated of drug per unit time.
• From this definition, clearance is the product of the blood flow (Q) to the organ and the
extraction ratio (E). The E is the fraction of drug extracted by the organ as drug passes
through.
• If the drug concentration in the blood (Ca)
entering the organ is greater than the drug
concentration of blood (Cv) leaving the
organ, then some of the drug has been
extracted by the organ.
• E is a ratio with no units.
• The value of E may range from 0 to 1
• An E of 0.25 indicates that 25% of the
incoming drug concentration is removed by
the organ as the drug passes through
The physiologic approach to organ clearance shows that the clearance from an
organ depends on

its blood flow rate and

its ability at eliminating the drug

Organ clearance measurements using the physiologic approach require invasive

techniques to obtain measurements of blood flow and extraction ratio.
 • Clearance is commonly used to describe first-order
drug elimination from compartment models such as
Non- the one-compartment model, in which the distribution
volume and elimination rate constant are well defined.
compartmental • Clearance estimated directly from the area under the
Methods plasma drug concentration-time curve using the
noncompartmental method is often called a “model-
independent” approach
The main advantages of this approach are that

(1) clearance can be easily calculated without making any assumptions

relating to rate constants (eg, distribution vs. elimination rate constants),

(2) volume of distribution is presented in a clinically useful context as it is

related to systemic exposure and the dose administered, and

(3) its estimation is robust in the context of rich sampling data as very
little modeling is involved.
• Using the noncompartmental approach, the
general equation therefore uses the area
under the drug concentration curve, [AUC]
0- ∞, for the calculation of clearance.
 • Clearance is a direct measure of elimination
from the central compartment, regardless of
the number of compartments.

Compartmenta
• The central compartment consists of the
plasma and highly perfused tissues in which
the drug equilibrates rapidly.
l Methods • The tissues for drug elimination, namely, the
kidney and liver, are considered integral parts
of the central compartment
Clearance is always the product of a rate constant and a
volume of distribution.

The clearance formulas depend upon whether the drug is

administered intravenously or extravascularly and range from
simple to more complicated scenarios.

Cl=k10×Vd
The Kidney
• The liver and the kidney are the two major drug-eliminating organs in the body.
• The kidney is the main excretory organ for the removal of metabolic waste products and
plays a major role in maintaining the normal fluid volume and electrolyte composition in
the body.
• To maintain salt and water balance, the kidney excretes excess electrolytes, water, and
waste products while conserving solutes necessary for proper body function.
• In addition, the kidney has two endocrine functions:
• (1) secretion of renin, which regulates blood pressure, and
• (2) secretion of erythropoietin, which stimulates red blood cell production.
 The kidneys are located in the peritoneal cavity.

The outer zone-------- cortex, and the inner--------medulla.

Considerations The nephrons -----------collectively responsible for the removal of
metabolic waste and the maintenance of water and electrolyte balance.

Each kidney contains 1-1.5 million nephrons.

Anatomic

Cortical nephrons have short loops of Henle that remain exclusively in

the cortex;

juxtamedullary nephrons have long loops of Henle that extend into the
medulla.

The longer loops of Henle allow for a greater ability of the nephron to
reabsorb water, thereby producing more concentrated urine.
 The kidneys represent about 0.5%
of the total body weight

and receive approximately 20%-

Blood Supply 25% of the cardiac output.

The filtration of blood occurs in the

glomeruli in Bowman’s capsule.
The kidney is supplied by blood via the renal artery--------subdivides into the
interlobar arteries------------ branching further into the afferent
arterioles--------afferent arteriole carries blood toward a single nephron into
the glomerular portion of the nephron (Bowman’s capsule)

From the Bowman’s capsule, the blood flows out---------efferent

arterioles------------second capillary network that surrounds the tubules
(peritubule capillaries and vasa recti), including the loop of Henle, where
some water is reabsorbed.
The renal blood flow (RBF) is the volume of blood flowing through the renal vasculature per unit of time.

RBF exceeds 1.2 L/min or 1700 L/d.

Renal plasma flow (RPF) is the RBF minus the volume of red blood cells present.

RPF is an important factor in the rate of drug filtration at the glomerulus.

RPF = RBF - (RBF × Hct)

• Hct is the fraction of blood cells in the blood, about 0.45 or 45% of the total blood volume.
• The relationship of RBF to RPF is given by a rearrangement of Equation

RPF = RBF (1 - Hct)

• Assuming a hematocrit of 0.45 and an RBF of 1.2 L/min and using the above equation,
• RPF = 1.2 - (1.2 × 0.45) = 0.66 L/min or 660 mL/min, or approximately 950 L/d.
• The average glomerular filtration rate (GFR) is about 120 mL/min in an average adult. The ratio GFR/RPF is the filtration fraction.
Regulation of Renal Blood Flow

Blood flow to an organ is directly proportional to the arteriovenous pressure difference (perfusion
pressure) across the vascular bed and indirectly proportional to the vascular resistance.

The normal renal arterial pressure is approximately 100 mm Hg and falls to approximately 45-60
mm Hg in the glomerulus.

This pressure difference is probably due to the increasing vasculature resistance provided by the
small diameters of the capillary network.

Thus, the GFR is controlled by changes in the glomerular capillary hydrostatic pressure.
• In the normal kidney, RBF and GFR remain relatively constant even with large differences
in mean systemic blood pressure
• The term autoregulation refers to the maintenance of a constant blood flow in the
presence of large fluctuations in arterial blood pressure.
• Because autoregulation maintains a relatively constant blood flow, the filtration fraction
(GFR/RPF) also remains fairly constant in this pressure range.
Glomerular Filtration and Urine
Formation

• A normal adult subject has a GFR of approximately 120 mL/min.

• About 180 L of fluid per day are filtered through the kidneys.
• In spite of this large filtration volume, the average urine volume is 1-1.5 L.
• Up to 99% of the fluid volume filtered at the glomerulus is reabsorbed.
• Besides fluid regulation, the kidney also regulates the retention or excretion
of various solutes and electrolytes.
 With the exception of proteins The filtrate contains some ions,
The essential nutrients and water
and protein-bound substances, glucose, and essential nutrients as
are reabsorbed at various sites,
most small molecules are filtered well as waste products, such as
including the proximal tubule,
through the glomerulus from the urea, phosphate, sulfate, and
loops of Henle, and distal tubules.
plasma. other substances.

Advances in molecular biology

have shown that transporters such
The urine volume is reduced, and as
Both active reabsorption and
the urine generally contains a high • P-glycoprotein and other efflux proteins
secretion mechanisms are
concentration of metabolic wastes can influence urinary drug excretion.
involved.
and eliminated drug products. • CYP enzymes are also present in the
kidney and can impact drug clearance by
metabolism.
Renal Drug • Drugs that are nonvolatile, are water soluble,
have a low molecular weight (MW), or are
slowly biotransformed by the liver are
Excretion eliminated by renal excretion.
• The processes by which a drug is excreted via
the kidneys may include any combination of
the following:
• Glomerular filtration
• Active tubular secretion
• Tubular reabsorption
 Glomerular filtration is a unidirectional
process that occurs for most small molecules
(MW < 500), including undissociated
(nonionized) and dissociated (ionized) drugs.
Protein-bound drugs behave as large
Glomerular molecules and do not get filtered at the
glomerulus.
filtration
The major driving force for glomerular
filtration is the hydrostatic pressure within the
glomerular capillaries.
• Glomerular filtration rate (GFR) is measured by using a drug that is eliminated primarily
by filtration only (ie, the drug is neither reabsorbed nor secreted).
• Clinically inulin and creatinine are often used for this purpose, although creatinine is also
secreted.
• The clearance of inulin is approximately equal to the GFR, which can equal 120 mL/min.
• The value for the GFR correlates fairly well with body surface area. Glomerular filtration
of drugs is directly related to the free or nonprotein-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
 • Active tubular secretion is an active transport process.
• As such, active renal secretion is a carrier-mediated system
that requires energy input because the drug is transported
against a concentration gradient.

Active
• The carrier system is capacity limited and may be
saturated.
• Drugs with similar structures may compete for the same
tubular carrier system.
• organic anion transporter, OAT

secretion • organic cation transporter, OCT).

• Drugs commonly used to measure active tubular secretion
include p-amino-hippuric acid and iodopyracet. ‘
• Active secretion is extremely rapid for these drugs, and
practically all the drug carried to the kidney is eliminated in
a single pass.
• 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.
• In contrast, 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.
 • Tubular reabsorption occurs after the drug is
filtered through the glomerulus and can be an
active or a passive process involving
transporting back into the plasma.
• If a drug is completely reabsorbed (eg,
glucose), then the value for the clearance of
Tubular the drug is approximately zero.

reabsorption • For drugs that are partially reabsorbed without

being secreted, clearance values are less than
the GFR of 120 mL/min.
• The reabsorption of drugs that are acids or
weak bases is influenced by the pH of the fluid
in the renal tubule (ie, urine pH) and the pKa
of the drug.
• Vegetable and fruit diets result in higher urinary pH, whereas diets rich in protein result in
lower urinary pH.
• Drugs such as ascorbic acid and antacids such as sodium carbonate may decrease (acidify)
or increase (alkalinize) the urinary pH, respectively, when administered in large quantities.
• By far the most important changes in urinary pH are caused by fluids administered
intravenously. Intravenous fluids, such as solutions of bicarbonate or ammonium chloride,
are used in acid-base therapy to alkalinize or acidify the urine, respectively.
• The excretion of these solutions may drastically change urinary pH and alter drug
reabsorption and drug excretion by the kidney.
 Renal Drug
Clearance Models for
The kidney excretion
concept clearance
methods

Summery
• Physiologic/Organ • Anatomical • Glomerular filtration
Clearance consideration • Active tubular
• Noncompartmental • Blood supply secretion
Methods • Regulation of Renal • Tubular
• Compartmental Blood Flow reabsorption
Methods • Glomerulus filtration
and urine formation