Pharmacokinetic

s continued…
Drug metabolism
and excretion
 Drug metabolism (biotransformation)

• It is the type of chemical reactions which leads to modification of drugs are

converted from one form to an other to make them more active ,less active
and finally inactive and to leave the body

• A mechanism for the conversion of non-polar molecules to polar metabolites

through oxidation, reduction or conjugation reaction
This is because polar metabolites are easier to excrete into the urine or bile
Metabolism mostly occurs
in the liver. For oral drugs,
first pass metabolism
takes place
 Results of biotransformation
Convert a toxin into a nontoxic molecule
Convert a pro - drug into an active molecule
Convert an active drug into an inactive drug that can then be eliminated via
urine or bile
Example
Drug Result Original product
Phenobarbitone Hydroxy Active drug Inactive metabolite
Phenobarbitone
Codeine Morphine Active drug Active metabolite
Levodopa Dopamine Inactive drug Active metabolite
• Site of metabolism
• Hepatic or Extrahepatic: lung ,blood ,skin , GIT, kidney.
• Cellular- endoplasmic reticulum (ER), mitochondria, cytosol, lysosomes, or
nuclear envelope or plasma membrane.

• Types of metabolism:

1. Oxidation, Conjugation (in the hepatic microsomal enzymes)

2. Acetylation, sulfation, Glutathione (GSH), alcohol/aldehyde

dehydrogenase, hydrolysis, Red-ox ( in the non hepatic microsomal
enzymes)
 Classification of
biotransformation
Phase I reactions
• Convert parent compound into a more polar (=hydrophilic) metabolite by adding
or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.)
• Change is due to oxidation/reduction or hydrolysis

• The new metabolite may retain biological activity

• different pharmacokinetic properties (short or long half life),

• they may become inactive or more toxic.

• CYP commonest enzyme used… classified according to
families.. E.g . CYP 2D6
Commonest used enzymes are CYP1A2, CYP2A6,
CYP2B6, CYP2C9, CYP2D6, CYP2E1, and
CYP3A4 accounting for approximately 15%, 4%,
1%, 20%, 5%, 10%, and 30%, respectively,
 CYP Nomenclature

• Family – CYP plus Arabic numeral (>40% aa sequence) e.g. CYP1

• Subfamily – additional upper case letter e.g. CYP1A

• Specific isoenzyme – additional Arabic numeral e.g. CYP1A2

• Gene encoding the enzyme – use italics e.g. CYP1A2

• Phase I metabolism is mainly catalyzed by CYP 450 isoenzyme in the
smooth endoplasmic reticulum of the cell (Microsomal
metabolism)

• There is an absolute requirement for molecular Oxygen

and NADPH (a reducing agent)

• flavoprotein, and cytochrome reductase.

• Oxidations include hydroxylation and dealkylations

• These enzymes may be induced or inhibited thus

affecting drug pharmacokinetics
E.G: grapefruit juice include furanocoumarins capable of inhibiting CYP enzymes =
inhibition of atorvastatin or cyclosporine

RESULT = REDUCED FIRST PASS METABOLISM OF THE DRUGS ATOVARSTATINE AND

CYCLOSPORINE

Another example of enzyme inhibitors: Polymorphism is the

occurrence of a variant allele
of a gene at a population
-Cimetidine and omeprazole frequency of < 1%,
resulting in altered
Examples of inducers expression or functional
activity of the gene product,
or both.
- Rifampicin, carbamazepine

Enzymes may also have genetic variations (polymorphisms) which cause

(Nonmicrosomal metabolism)

• Hydrolysis: phase I reaction involving addition of a water molecule with subsequent

bond breakage;

• Enzymes include esterases and amidases

• Genetic polymorphism may exist with pseudocholinesterases thus affecting

metabolism of local anesthetics and succinylcholine

• Enzymes like Monoamine oxidases are into the metabolism of endogenous amine
neurotransmitters (dopamine, norepinephrine, and serotonin); metabolism of
exogenous compounds (tyramine)

• Alcohols are metabolized to aldehydes and then to acids by dehydrogenases and

 Examples of some PHASE 1 reactions

Hydroxylation -CH2CH3 -CH2CH2OH

Oxidation -CH2OH -CHO -COOH
O-de-alkylation -CH2OCH2- -CH2OH + -CHO

N-de-alkylation -N(CH3)2 -NHCH3 + CH3OH

N-oxidation -NH2 -NHOH

Oxidative deamination NH2-CH2CHCH3  -CHCOCH3 + NH3
Phase 2 reactions – conjugation
• Conjugation with endogenous substrate to further increase aqueous solubility
via the activity of transferases.
• bound by polar molecules or modified by functional groups
• in almost all cases results in detoxication
• conjugate is readily eliminated by the kidney or if the molecular weight is more
than 300 it is eliminated by bile
Factors that
affect drug
metabolism
 Enzymes
involved in
biotransform
ation
Elimination (excretion) of
drugs
Excretion is the passage out of systemically absorbed drug.
• The major modes of drug elimination are:
• Biotransformation to inactive metabolites
• Excretion via the kidney
• Excretion via other modes, including the bile duct, lungs, and sweat

• The excretion of drug in milk is not important for the mother, but the suckling infant
inadvertently receives the drug. Most drugs enter breast milk by passive diffusion

• The time to eliminate 50% of a given amount (or to

decrease plasma level to 50% of a former level) is called
the elimination half-life (t1/2).

• t(1/2)= 0.7xV/Cl
Clinical significance of half life
• Determine the time a steady state is achieved (amount eliminated is equal to
amount administered within the dose interval)
• Determine the duration of action
• Determine the frequency of administration
Drug Clearance
• Clearance (Cl) is the volume of blood cleared of drug per unit of time
CL = Rate of elimination/C (plasma concentration)

• With zero-order elimination rate, a constant amount of drug is eliminated per

unit time. Elimination rate is indecent of plasma concentration.

Ex: If 80 mg is administered and 10 mg is eliminated every 4 h, the time course of

drug 4hrs 4hrs
elimination is: 4hrs
• Drugs with zero-order elimination have no fixed half-life (t1/2 is a variable)

Examples of drugs with Zero-order pharmacokinetics

• Alcohol (except at low doses)

• Salicylates at toxic doses

Once a drug changes to zero order pharmacokinetics, an increase in dose

translates into toxicity
First Order Pharmacokinetics

• With first-order elimination rate, a constant fraction of the drug is

eliminated per unit time (t1/2 is a constant).

• Graphically, first-order elimination follows an exponential

decay versus time.

• Rate of elimination is directly proportional to plasma

concentration
Elimination
• For most drugs elimination follows 1st order kinetics
Given a one drug compartment distribution and first
order elimination, if the drug is given i.v. a semilog
plasma concentration-time plot
The plot has two slopes.
• initial rapidly declining (alpha) phase—due to
distribution.
• later less declined (beta ) phase—due to
elimination.
1 t½ – 50% drug is eliminated.
2 t½ – 75% (50 + 25) drug is eliminated.
3 t½ – 87.5% (50 + 25 + 12.5) drug is eliminated.
4 t½ – 93.75% (50 + 25 + 12.5 + 6.25) drug is
eliminated.
Therefore, the drug is completely eliminated after
4-5 half lives
 DRUG DISPOSITION AFTER
ORAL DOSE

Co
Log Drug Concentration 5.0
2.0

1.0

0.5
T1/2
0.2
0.1
2 4 6 8 10
Time
• Elimination rate (R) is the amount of drug eliminated from the body per unit
time;
• R = dCp/dt;
• This parameter is important because at steady state, the elimination rate
equals rate of drug administration (dosing rate);
• Steady state is reached either when rate in = rate out or when values
associated with a dosing interval are the same as those in the succeeding
interval.
• Useful in designing a dosing regimen
Clearance (CL)
• A measure of the efficiency with which a drug is irreversibly removed
from the body
• *Clearance (Cl) is the volume of plasma completely cleared of the
drug per unit time;
• CL = Elimination rate (R)/Cp (5)
• R (= Dosing rate) = CL . Cp (6)
 Clearance (CL)

• A measure of the efficiency with which a drug is irreversibly removed

from the body

• *Clearance (Cl) is the volume of plasma completely cleared of the

drug per unit time;

• CL = Elimination rate (R)/Cp

• R (= Dosing rate) = CL . Cp
 RATIONAL DOSING REGIMEN
• Based on a targeted concentration that will produce a desired
therapeutic effect

• Typically drugs are administered in such a way as to maintain a

steady state.

• This needs calculation of maintenance doses

• Clearance (CL) is used in defining a rational steady state drug dosage

regimen (maintenance doses)
Dosing Rate (DR) = Rate of Elimination (Ke)

DR = CL x Targeted Concentration (TC)

Maintenance Dose = DR x Dosing interval

 Example for
Theophylline in Asthma:
Target needed = 10 mg/L
Clearance = 2.8 L/h/70 kg
Bioavailability (by IV) = 1

Dosing Rate = CL x TC
= 2.8 L/h/70 kg x 10 mg/L
= 28 mg/h/70 kg

This will be the proper continuous infusion rate

 If the drug is given orally twice daily, with F=0.96, then

Maintenance Dose (MD) = DR x Dosing interval

F
Example:

MD = 28 mg/h x 12 hours
0.96
MD = 350 mg every 12 hours

Calculate the maintenance dose for 8 hrly dosing and F = 0.60

 Clearance
• Total body clearance (CL) is the sum of individual clearance for the different
organs e.g. liver (CLL), kidneys (CLR);

• Specific organ clearance is determined by the blood flow (Q) and extraction
ratio (E)

• Extraction ration = (Ca – Cb)/Ca

• Organ Clearance = Q.(Ca – Cb)/Ca

• Ca => conc of drug in blood entering organ

• Cb => conc of drug in blood leaving organ

 Rate of elimination
CLrenal = Cp

Rate of elimination
CLliver = Cp

Rate of elimination
CLother =
Cp

CLsystemic = CLliver + CLrenal + CLother

Flow Limited &
Capacity Limited CL
• Flow limited clearance – for drugs with high E, CL
depends on Q (blood flow rate)
• E.g. propranolol, lidocaine, morphine

• Capacity limited clearance – for drugs with very low

E, CL is almost independent of blood flow rate (Q); CL
is more dependent on organ capacity to extract the
drug
• E.g. phenytoin, warfarin, quinidine
EXERCISE 2.
• Five healthy subjects A, B, C, D, and E received
intravenous bolus doses of drugs as indicated in the
table given. Venous blood samples were collected and
analysed for plasma drug concentrations at 0.5, 1, 2, 4,
6, 8 and 10 hrs post-injection.
• i. Use the data provided to construct plasma drug
concentration (Cp) vs time (t) curves for each subject.
• ii. Specify whether the kinetics is zero order or 1st order
• iii. Determine the plasma concentrations at zero time
(CpO), t ½, Vd, and Kel for each patient.
Subjects A B C D E
Doses given 150 mg 300 mg 150 mg 150 mg 250 mg

Time (hr) Cp (mg/L) Cp Cp Cp (mg/L) Cp

(mg/L) (mg/L) (mg/L)
0 ? ? ? ? ?
0.5 11.1 7.46 5.58 3.41 6.05
1 9.52 6.24 5.88 3.01 4.57
2 6.71 5.04 4.43 2.37 3.44
4 3.87 3.28 3.37 1.48 1.67
6 2.10 2.07 2.68 0.93 0.94
8 1.15 1.10 1.75 0.58 0.43
10 0.57 0.63 1.35 0.38 0.23