Non-Linear Pharmacokinetics: Biopharmaceutics (Ashik Sir)

Biopharmaceutics (Ashik Sir)
Non-linear Pharmacokinetics
Question: Derivation of Michaelis-Menten Equation/Non-Liner pharmacokinetic model
Reaction Model:
The enzyme reacts with the substrate by binding to its active site to form the enzyme substrate
complex, ES. That reaction followed by the decomposition of ES to regenerate the free E and the
new product P.
Michaelis-Menten Equation:
Here, Vo = Initial reaction velocity

Vmax = Maximum velocity
Km = Michaelis constant = (K-1 + K2/K1)
= Reflects the capacity of the enzyme system, equals to the drug concentration or
amount of the drug in the body at 0.5 Vmax
ASSUMTION 1: Substrate [S] is very large compared to [E], so that when all E is bound in the
form ES, there is still an excess of S.
By the loss of mass action, the rate of formation of ES from E + S is proportional to [E] × [S]
ASSUMTION 2: Conditions are such that there is very little accumulation of P (product). So that,
the formation of ES from E + P is negligible. The rate of ES is given by –
ASSUMTION 3: The rate of breakdown of ES very rapidly equal to the rate of formation of ES.
This is the steady state assumption.
Or, K1 [E] [S] = K – 1 [ES] + K2 [ES] {From the equation 1 and equation}
Or, K1 [E] [S] = (K1 + K2) [ES]
Steady state assumption → [ES] is constant. So,

Formation of ES = Loss of ES.
MD. ASIF HASAN NILOY

B.Pharm24Batch; 8th Semester Page 1|9
We know that –
Michaelis constant Km is the substrate concentration at which the reaction rate is at half maximum
& is an inverse measure of the substrate’s affinity to the enzyme.
So,
The total amount of enzyme in the system must be the same throughout the experiment but it can
either be free (unbound) E or in complex with substrate, ES. If we term the toral enzyme Et, this
relationship can be written out:
[Et] = [E] + [ES] (4)
From equation 3 and equation 4 we can write –
Or, [Et] [S] – [ES] [S] = KM [ES]

Or, [Et] [S] = KM [ES] + [ES] [S]
Or, [Et] [S] = ([S] + KM) [ES]
Vo is determined by the breakdown of ES to form product, which is denoted by [ES].

Vo = K2 [ES] (6)
From the equation 5 and equation 6 we can write,
The maximum rate, which can call Vmax, would be achieved when all of the enzyme molecules
have substrate bound. Under the conditions when [S] is much greater than [E], it is fair to assume
that all E will be in the form ES. Therefore [Et] = [ES]. Thinking again about equation 6, we could
substitute the term Vmax for Vo and [Et] for [ES]. This would give us –
Vmaax = K2 [Et]
From equation 7,

Question: Why Michaelis-Menten Equation is termed mixed order kinetics?
When the drug concentration is low relative to the enzyme concentration, there are abundant
enzymes to catalyze the reaction, and the rate of metabolism is a first-order process.
So, If KM >>> [S] we can write–
KM + [S] = KM
From Michaelis-Menten Equation
Here,
KM = [S]
Or, KM + [S] = [S] + [S] = 2[S]
∴ Vo = Vmax / 2
Saturation of the enzyme usually occurs when the plasma drug concentration is relatively high,
all the enzyme molecules become complexed with drug, and the reaction rate is at a maximum
rate; the rate process then becomes a zero-order process.
So, If KM <<< [S] we can write –
KM + [S] = [S]
From Michaelis-Menten Equation
From the equation Vo = Vmax

Because of following 1st order and second order this kinetics is termed mixed order.
Question: From the following equation define following terms –
1) Turnover Number: Number of substrate molecules converted into product by one molecule
of enzyme active site per unit time, when enzyme is fully saturated with substrate.
K2 = kcat = turnover number
2) KM: Substrate concentration at which velocity (V0) exactly ½ of Vmax.
K – 1 + K2
KM = Michaelis constant =
K1
It is termed Michaelis – Menten Constant of the drug in the body which reflects the capacity
of the enzyme system, equals to the drug concentration or amount of the drug in the body at
0.5 Vmax and written as
KM also known as substrate concentration when V0 = ½ Vmax
Importance of KM:
[E] [S]
KM =
[ES]
(1) KM determines the affinity of an enzyme for its substrate, lesser the KM more the affinity
and vice versa.
(2) KM value helps in determining the true substrate for the enzyme.
Question: Define non – linear pharmacokinetic. Why it is called dose dependent

pharmacokinetics?
Non-linear Pharmacokinetics: The first order kinetics is usually transformed into mixture of
first order and zero order rate process and the pharmacokinetic parameters are changed with
the size of the administered dose. Pharmacokinetics of these are said to be non-linear/mixed
order/capacity-limited/dose dependent pharmacokinetic.
Dose-dependent pharmacokinetics:
Phenytoin → 300 mg (50% increase) → 450 mg → CSS (10X increase)
Phenytoin undergoes capacity-limited kinetics at therapeutic drug concentrations in the body.
At steady state, the rate of drug metabolism is assumed to be the same as the rate of drug input
(dose/day). Therefore, Equation may be written for drug metabolism in the body similar to the
way drugs are metabolized in vitro.
1st Condition: KM >>> C

KM + C = KM

2nd Condition: KM <<< C
KM + C = C
∴ V0 = Vmax
Linear pharmacokinetic is non-dose dependent pharmacokinetics
Question: Write down the units of Vmax and KM

Vmax = Elimination rate
= mg/time
= mg/day
= concentration/time
= mg/L/day
= mg/L/hour
KM = Units of concentration
= dose/volume
= mg/L
Question: For the following equation.
(a) What do you mean by the term “Enzyme-Substrate Complex”? Write down its
significance.
Enzyme-Substrate Complex: Substrate binds to enzymes binding site to form a complex
which is termed as enzyme substrate complex.
Significance of it:
[E] [S]
KM =
[ES]

(1) KM determines the affinity of an enzyme for its substrate, lesser the KM more the affinity
and vice versa.
(2) KM value helps in determining the true substrate for the enzyme.
(b) Write the rate equation for the production of ES?

Rate of formation of ES complex = Formation of ES – Breakdown of ES
= K1 [E] [S] – K – 1 [ES] – K2 [ES]
(c) What is the rate of product formation from ES?
; Here, v = elimination or metabolism rate

(d) If all the enzyme is bound to substrate, what is the effect of adding more substrate on
the forward rate of reaction?
Etotal = ES + E
= ES + 0
∴ Etotal = ES
V = K2 [ES]
Vmax = K2 [Et]
From here we can say that enzyme works at its maximum rate and it cannot faster.
A given drug is metabolized by capacity-limited pharmacokinetics. Assume KM is

50𝛍g/mL, Vmax is 20𝛍g/mL per hour and apparent VD is 20 L/kg.
a) What is the reaction order for the metabolism of this drug when given in a single IV dose of
10 mg/kg?
Here,
KM = 50𝛍g/mL
Vmax = 20𝛍g/mL per hour
VD = 20 L/kg = 20,000mL/kg
We know,
IV dose = 10 mg/kg
= 10,000 𝛍g/kg
VD = 20 L/kg
= 20,000mL/kg

Again we know that,
Because KM = 50 𝛍g/mL we can write, CP <<< KM and we can say that the reaction rate is first
order.
So, the above equation can reduce to
b) How much time is necessary for the drug to be 50% metabolized?

Because of both Vmax and KM are constant, the metabolism rate is proportional to the drug
concentration and a constant (first order process) in this region.
Now,
For the first order reaction,
RM is a 32 years old, 80kg male is being seen in the Neurology clinic. Prior to his last visit
he had been taking 300 mg of phenytoin daily; however, because his seizers were poorly
controlled and because his plasma concentration was only 8mg/K, his dose was
increasing to 360mg daily. Now the complain of minor CNS side effects and his reported
plasma phenytoin concentration is 20mg/L. Renal and hepatic function are normal.
Assume that both of the reported plasma concentrations represent steady state and that the
patient has copied with the prescribed dosing regimen.
a) Calculate RM’s apparent VM and KM.
b) Calculate RM’s a new daily dose of phenytoin that will result in a steady state level of about
15mg/L.

Here,
32 year Patient weight = 80kg
Dose of phenytoin = 300mg/day = R1
Steady state plasma concentration CSS (1) = 8mg/L
Dose of phenytoin = 360mg/day = R2
Plasma concentration CSS (2) = 20mg/L
We know,
⇒ R1 × KM + R1 × CSS 1 = VMax × CSS 1

⇒ 300 × KM + 300 × 8 = VMax × 8
⇒ 37.5 KM + 300 = VMax [Diving by 8] --------------------------------- (1)
Again,
⇒ R2 × KM + R2 × CSS 2 = VMax × CSS 2

⇒ 350 × KM + 350 × 20 = VMax × 20
⇒ 17.5 KM + 350 = VMax [Diving by 20] ------------------------------- (2)
Now subtracting equation (2) from (1) we can write,
(37.5 – 17.5) KM + (300 – 350) = 0
⇒ 20 KM = 50
∴ KM = 2.5mg/L
Now plotting the value of KM to equation (1)
(37.5 × 2.5) + 300 = VMax
∴ VMax = 393.75mg/day
c) When CSS 55 calculate the dose of that drug.
We know,



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Biopharmaceutics (Ashik Sir)

Here, Vo = Initial reaction velocity

Steady state assumption → [ES] is constant. So,

MD. ASIF HASAN NILOY

Or, [Et] [S] – [ES] [S] = KM [ES]

Vo is determined by the breakdown of ES to form product, which is denoted by [ES].

MD. ASIF HASAN NILOY

From the equation Vo = Vmax

Question: From the following equation define following terms –

Question: Define non – linear pharmacokinetic. Why it is called dose dependent

1st Condition: KM >>> C

MD. ASIF HASAN NILOY

Question: Write down the units of Vmax and KM

Question: For the following equation.

MD. ASIF HASAN NILOY

(b) Write the rate equation for the production of ES?

; Here, v = elimination or metabolism rate

A given drug is metabolized by capacity-limited pharmacokinetics. Assume KM is

MD. ASIF HASAN NILOY

So, the above equation can reduce to

b) How much time is necessary for the drug to be 50% metabolized?

For the first order reaction,

MD. ASIF HASAN NILOY

⇒ R1 × KM + R1 × CSS 1 = VMax × CSS 1

⇒ R2 × KM + R2 × CSS 2 = VMax × CSS 2

MD. ASIF HASAN NILOY

MD. ASIF HASAN NILOY

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