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PHARMACOKINETICS | DRUG CLEARANCE

Pharmacokinetics | Drug Clearance Medical Editor: Sarah Abimhamed

OUTLINE
I) START HERE (A) FIRST-ORDER ENZYMATIC KINETICS VI) REVIEW QUESTIONS
II) MECHANISM OF DRUG CLEARANCE (B) ZERO-ORDER ENZYMATIC KINETICS VII) REFERENCES
(A) CLEARANCE AND ELIMINATION (C) ENZYME SATURATION
(B) EFFECT OF ORGAN DYSFUNCTION (D) STEADY STATE
(C) FORMULA OF CLEARANCE IV) DRUG CLEARANCE PRACTICE PROBLEMS
III) ELIMINATION KINETICS V) SUMMARY

I) MECHANISM OF DRUG CLEARANCE

(A) CLEARANCE AND ELIMINATION
CLEARANCE is the rate of ELIMINATION of a prticular
drug over the plasma concentration of the drug.
o ELIMINATION is the combination of:

Figure 1: Main organs contributing to the total clearance of

drugs
(B) EFFECT OF ORGAN DYSFUNCTION
Basically, clearance is dependent on elimination, which is
dependent on the function of two primary organs; the liver Example: a drug is primarily cleared by the kidney, about
and the kidneys. 95%, and the remaining 5% is cleared by the liver. If the
o Therefore, if a dysfunction develops of the kidneys or patient taking this drug, and has chronic kidney disease
the liver, the clearance rate decreases (↓) (CKD), this drug will not be cleared by the kidney
primarily, and this leads to an increase in the
concentration of the drug because the rate of elimination
is decreased

Table 1: Example of a patient with CKD

Primary organ of drug Kidney (95%)
clearance
Patient case Chronic Kidney Disease
[Drug] (↑)
Rate of Elimination (↓)

(C) FORMULA OF CLEARANCE

The first principle of clearance is that clearance is the rate of elimination of a drug over the concentration of this drug in the
plasma [C]P
o Another principle says that clearance is also dependent on the volume of distribution (Vd) times a constant (0.693 ~ 0.7),
divided by the half-life of the drug (T1/2)

Figure 3: Formula of clearance of drugs

Half-life effect on the clearance:

o If the half-life of the drug is high, the clearance is
decreased, and vice versa
o Half-life and clearance values of the drug are
Figure 4: Clearance of the drug and its half-life are inversely
inversely proportional proportional

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 II) ELIMINATION KINETICS
The rate of elimination of drugs may be zero order (i.e., constant regardless of concentration) or first order (i.e., proportional to
the concentration).

Test tip: Questions may be about:

o Comparing graphs
o Terminologies of constant parameters
o Proportion of drug to rate of elimination

(A) FIRST-ORDER ENZYMATIC KINETICS (B) ZERO-ORDER ENZYMATIC KINETICS

Most drugs, with respect to their biochemical profile, Only a number of drugs work under zero-order enzymatic
work under first-order enzymatic kinetics kinetics, and those include:
o Phenytoin (PHT; anti-seizure medication)
o Ethanol (EtOH; Alcohol)
o Aspirin (ASA; NSAID)

Half-life of these drugs is variable, however, the amount

Assuming that every hour, 50% (fraction) of the drug is of drug that is eliminated per time unit is constant, which
eliminated (E: 50%/hr.), the graph representing the rate means the rate of elimination is constant.
of elimination will appear curved (exponential) o Assuming 100 mg/L of the drug is administered, and
every hour 25 mg (amount) of the drug is eliminated,
the graph representing the rate of elimination will
appear linear.

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Figure 5: First-order enzymatic kinetics graph
Figure 7: Zero-order enzymatic kinetics graph

The amount of drug given to a patient (Drug

concentration; [Drug]) is directly proportional to the rate
of elimination, and this is unique to first-order kinetics.
The rate of elimination for these drugs is independent of
concentration of the drug given

Figure 6: First-order enzymatic kinetics equation

Figure 8: Zero-order enzymatic kinetics equation and properties

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(D) STEADY STATE

(C) ENZYME SATURATION
Steady state is the condition where the rate of drug
Increasing the concentration of the drug that follows first-
elimination equals the rate of administration.
order kinetics leads to increased rate of elimination.
o It is important to understand the time it takes to reach
o Why? Because there are enzyme sites available for
steady state.
the drug to bind on and be metabolized and excreted.
o The time to reach steady state is same time needed
to eliminate 95% of the drug. The concept can be
clarified using the first-order kinetics, where it takes
Increasing the concentration of the drug that follows zero- around 4-5 hours to eliminate 95 mg of a 100 mg/L
order kinetics will not increase the rate of elimination. administered drug.
o Why? Because the enzyme that metabolizes this drug  Similarly, it would take 4-5 half-lives to eliminate
would already be saturated, at Vmax (maximum 95% of the drug and arrive at the steady state.
velocity of the reaction)
o The flat portion of the graph refers to zero-order
kinetics

Figure 10: The time required to reach the steady state

(eliminate 95% of the drug) is around 4-5 half-lives

Figure 9: Graph of the rate of elimination of drugs of first-order

kinetics and zero-order kinetics, and the enzyme saturation
comparison.

III) DRUG CLEARANCE PRACTICE PROBLEMS

Question: Factors affecting clearance

1) A 55-year-old woman is brought to the emergency 2) A pharmacokinetic study of a new antihypertensive

department because of seizures. She has a history of drug is being conducted in healthy volunteers. The
renal disease and currently undergoes dialysis. She half-life of the drug after administration by
receives intravenous infusion of antiseizure Drug. continuous intravenous infusion is 12 hours. Which
Which of the following is likely to be observed with of the following best approximates the time for the
use of Drug Ninja in this patient? drug to reach steady state?
Half-life Dosage a) 24 hours
a) ↑ ↑
b) ↓ ↓ c) 72 hours
c) ↑ ↔ d) 120 hours
d) ↑ ↓ e) 240 hours
e) ↔ ↔ Answer: b
Answer: d o Explanation: It takes about 4-5 half-lives for a drug to
o Explanation: Since the patient has a renal disease, be able to reach a steady state concentration.
the clearance is likely going to decrease, and since 12 hours x 4 = 48 hours
clearance has an inversely proportional relationship
with half-life of the drug, the half-life of the drug is
going to increase.
o As the half-life of the drug increases, there will be risk
of accumulation of the drug which may lead to
toxicity. Therefore, the dosage of the drug must be
lowered.

IV) SUMMARY

First-order enzymatic kinetics Zero-order enzymatic kinetics

Rate of Elimination Dependent on the concentration of the drug [Drug] Independent of the concentration of
the drug
Elimination kinetics Rate of elimination is directly proportional with the half- Rate of elimination is constant
equation life of the drug (T1/2)
Elimination kinetics Curved (exponential) graph Linear graph
graph
Half-life (T1/2) Constant Variable
Drugs Most drugs Phenytoin (PHT), Alcohol (EtOH),
Aspirin (ASA)

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 V) REVIEW QUESTIONS VI) REFERENCES
1) Which of the following organs is crucial in the ● Tao and Bhushan, Vikas. First Aid for the USMLE Step 1 2022,
Thirty second edition. New York: McGraw-Hill Education, 2022.
elimination of drugs?
a) Kidney ● Raffa, Robert B, Scott M. Rawls, Elena P. Beyzarov, and Frank
b) Lungs H. Netter. Netter's Illustrated Pharmacology. 2013.
c) Salivary glands ● Ritter, James. Rang and Dale's Pharmacology. Ninth edition.
d) Lacrimal glands Edinburgh: Elsevier, 2020.

2) Clearance is equal to? ● Brown, Morris J., Pankaj Sharma, Fraz A. Mir, and Peter N.
a) Drug concentration over rate of elimination Bennett. Clinical Pharmacology. 12th ed. Philadelphia: Elsevier
b) Rate of elimination over drug concentration [Imprint] Elsevier - Health Sciences Division, 2018.
c) Rate of elimination over distribution volume
d) Distribution volume over the constant 0.7 ● Goodman & Gilman's: The Pharmacological Basis of
Therapeutics, 13e Brunton LL, Hilal-Dandan R, Knollmann BC.
3) The fraction of the drug that is eliminated per unit Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), Eds
(2018)
time is constant, this principle is related to which
type of elimination kinetics? ● Lippincott Illustrated Reviews: Pharmacology. 6th ed.
a) Zero-order kinetics Philadelphia, PA: Wolters Kluwer, (2015)
b) First-order kinetics
● Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic
c) Second-order kinetics & Clinical Pharmacology, 14e. McGraw Hill (2018)
d) None of the above
4) What is the correct sentence with respect to first-
order kinetics?
a) The amount of drug given to a patient is directly
proportional to the rate of elimination
b) The amount of drug given to a patient is inversely
proportional to the rate of elimination
c) The rate of elimination for these drugs is
independent of concentration of the drug given
d) Both a & c
5) What is the portion of the drug where it is considered
that the drug has reached steady state?
a) 75%
b) 85%
c) 95%
d) 100%
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6) Which of the following drugs do not follow zero-
order kinetics?
a) Phenytoin
b) Ethanol
c) Salicylates
d) Paracetamol

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