CHAPTER NO: 4
DRUG CLEARANCE
BIOPHARMACEUTICS and
PHARMACOKINETICS
NOTE BY
DR. FAHAD PERVAIZ
ASSOCIATE PROFFESSOR
THE ISLAMIA UNIVERSITY OF BAHAWALPUR
PAKISTAN
DRUG ELIMINATION
• Drug elimination refers to the irreversible removal of drug from the body by all routes of
elimination
• Drug elimination is usually divided into two major components:
1. excretion
2. biotransformation
Drug excretion
• Drug excretion is the removal of the intact drug.
• Nonvolatile and polar drugs are excreted mainly by renal excretion, a process in which
the drug passes through the kidney to the bladder and ultimately into the urine.
• Other pathways for drug excretion may include the excretion of drug into bile, sweat,
saliva, milk (via lactation), or other body fluids.
• Volatile drugs, such as gaseous anesthetics, alcohol, or drugs with high volatility, are
excreted via the lungs into expired air
Biotransformation or drug metabolism
• Biotransformation or drug metabolism 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 (eg, ester hydrolysis).
• 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.
DRUG CLEARANCE
• Drug clearance is a pharmacokinetic term for describing drug elimination from the body
without identifying the mechanism of the process.
• Clearance may be defined as the volume of fluid removed of the drug from the body per
unit of time.
•
•
•
• Drug clearance (also called body clearance or total body clearance, and abbreviated as
Cl or ClT) considers the entire body as a single drug-eliminating system from which many
unidentified elimination processes may occur.
• Instead of describing the drug elimination rate in terms of amount of drug removed per
unit of time (eg, mg/h), drug clearance is described in terms of volume of fluid removed
from the drug per unit of time (eg, L/h).
• The units for clearance are sometimes in milliliters per minute (mL/min) but most often
reported in liters per hour (L/h).
• 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.
DRUG CLEARANCE and Dose
• Clearance is even more important clinically than a half-life for several reasons. First and
foremost, clearance directly relates to the systemic exposure of a drug (eg, AUC 0-inf),
making it the most useful PK parameter clinically as it will be used to calculate doses to
administer in order to reach a therapeutic goal in terms of exposure.
Cl = Dose / AUC0-inf
CLEARANCE MODELS
1) Physiological clearance
2) Compartment model
3) Model independent (non-compartment)
PHYSIOLOGICAL ORGAN CLEARANCE
• 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 (ER).
• The ER is the fraction of drug extracted by the organ as drug passes through.
Cl (organ) = Q (organ) × E (organ)
• 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.
• The E is Ca - Cv divided by the entering drug concentration (Ca), as shown in Equation.
•
• E is a ratio with no units. The value of E may range from 0 (no drug removed by the
organ) to 1 (100% of the drug is removed by the organ). 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 clearance shows that clearance depends on the blood flow
rate and
• The ability of the organ to eliminate drug,
• whereas the classical definitions of clearance is that
• A constant or static fraction of the volume in which the drug is contained is removed per
unit time by the organ.
• However, clearance measurements using the physiologic approach require invasive
techniques to obtain measurements of blood flow and extraction ratio.
• The physiologic approach has been used to describe hepatic clearance, which is discussed
under hepatic elimination.
Noncompartmental Methods
• Clearance estimated directly from the area under the plasma drug concentration-time
curve using the noncompartmental method is often called a “model-independent”
approach as it does not need any assumption to be set in terms of the number of
compartments describing the kinetics or concentration-time profile of the drug under
study.
• The noncompartmental approach is based on statistical moment theory
• The main advantages of this approach are:
• (1) clearance can be easily calculated without making any assumptions relating to rate
constants (e.g., 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.
• Clearance can be determined directly from the time-concentration curve by
D is the dose administered, F is the bioavailability
factor associated with the administration route
used of the drug product .
Because [AUC]0-∞ is calculated from the drug concentration-time curve from zero to
infinity using the trapezoidal rule, no model is assumed until the terminal phase after the
last detectable concentration is obtained (Ct). To extrapolate the data to infinity to obtain
the residual [AUC]t0-∞ or Cpt/ k , first-order elimination is usually assumed.
• At steady state, when the concentration-time profiles between administered doses become
constant, the amount of drug administered over the dosing interval is exactly equal to the
amount eliminated over that dosing interval (t). The formula for clearance therefore
becomes:
•
• Equation can be derived that following a constant intravenous infusion, the steady-state
concentration (Css) will then be equal to“rate in,” the administration dosing rate (R0),
divided by “rate out” or the clearance:
•
Compartmental Methods
• Clearance is a direct measure of elimination from the central compartment, regardless of
the number of compartments.
• The central compartment consists of the plasma and highly perfused tissues in which
drug equilibrates rapidly. The tissues for drug elimination, namely, 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.
• Drug that is well described pharmacokinetically with a one-compartment model:
• After intravenous administration, such a drug will exhibit a concentration-time profile
that decreases in a straight line when viewed on a semi-log plot and would therefore be
well described by a mono-exponential decline.
• This is the simplest model that can be used and often will describe well the
pharmacokinetics of drugs that are very polar and that are readily eliminated in the urine.
• Clinically, aminoglycoside antibiotics are relatively well characterized and predicted by a
one-compartment model.
•
• After oral administration the formula for clearance is exactly the same but a Cl/F is
calculated. There is also an absorption process in addition to an elimination one. If the
absorption process is faster than the elimination, the terminal rate constant, ƛz will
describe the elimination of the drug.
• It is sometimes not possible to know if a drug exhibits a slower absorption than
elimination. In these cases, it is always best to refer to ƛz as the “terminal”
If the absorption of the drug is much slower than the elimination process (eg, often the case with
modified release formulations), then the terminal rate constant, ƛz, will be reflective of the
absorption and not the elimination.
Drug that is well described pharmacokinetically with a two-compartment model:
• After intravenous administration, such a drug will exhibit a concentration-time profile
that decreases in a profile that can be characterized by two different exponentials or two
different straight lines when viewed on a semilog plot.
• This model will describe well the pharmacokinetics of drugs that are not so polar and
distribute in a second compartment that is not so well perfused by blood or plasma.
Clinically, the antibiotic vancomycin is relatively well characterized and predicted by a
two-compartment model.
•
•
• where k10 is the rate constant describing the disappearance of the drug from its central
volume of distribution (Vc).
• The distributional clearance (Cld) describes the clearance occurring between the central
(Vc) and the peripheral compartment (Vp), and where the central compartment includes
the plasma and the organs that are very well perfused, while the peripheral compartment
includes organs that are less well perfused.
• The concentration-time curve profile will follow a biexponential decline on a semilog
graph and the distributional rate constant (ƛ1) will be describing the rapid decline after IV
administration that describes the distribution process, and the second and last exponential
(ƛz ) will describe the terminal elimination phase.
• Relationship with the noncompartmental approach after IV administration:
•
• It is often stated that clearances and volumes are “independent” parameters, while rate
constants are “dependent” parameters.
Relationship of Clearance and Elimination Half-Life
If we know the Clearance, we can determine Half-Life (t1/2) of a drug through a simple relation
ClT = kVD
And
k = 0.693/t1/2
Therefore, by substitution
0.693 VD
Cl T =
t 1/ 2
