Introduction Have you ever thought about how does medicine move throughout your body? In this post, we will learn about the process of ADME in pharmacokinetics. Suppose you have a headache and you take Disprin (Aspirin) tablet. But do you know how Dispirin knows where to go in your body or where the problem is? Here, we will understand the entire journey of medicine in the human body. This post will be fascinating and informative for medical students, physicians, pharmacists, nurses, and general people. So, keep reading to learn about ADME in pharmacokinetics – What is meant by ADME in pharmacokinetics? Pharmacokinetics is the branch of pharmacology (study of medicine) that deals with how drugs move through the body. If we split the term pharmacokinetics. In Greek, “Pharmakon” means drug (or medicine), and “kinetics” implies movement. In other words, pharmacokinetics is simply a movement of medicine in the body. All medicines are indeed drugs, but not all drugs are medicines. So, medicine is considered a drug. The pharmacokinetics would be basically an ADME study. The ADME in pharmacokinetics refers to absorption, distribution, metabolism, and excretion. Every medicine must follow the ADME process (absorption, distribution, metabolism, and excretion). Here, ADME in pharmacokinetics - A represents absorption – medicine gets into the bloodstream. D represents distribution – medicine moves from the bloodstream to tissue (or site of action) M represents metabolism – biotransformation of medicine (drug change from one form to another form) E represents excretion – medicine eliminate from the body via urine/stool What are the 4 steps of pharmacokinetics? For a good pharmacokinetic profile, a medicine must complete 4 steps of pharmacokinetics in the human body, i.e., ADME. Step 1 Absorption, Bioavailability & Prodrug Step 2 Distribution Step 3 Metabolism Step 4 Excretion

1. ADME in Pharmacokinetics: how does medicine
travel through the body?
Introduction
Have you ever thought about how does medicine move throughout your body? In
this post, we will learn about the process of ADME in pharmacokinetics.
Suppose you have a headache and you take Disprin (Aspirin) tablet. But do you
know how Dispirin knows where to go in your body or where the problem is?
Here, we will understand the entire journey of medicine in the human body. This
post will be fascinating and informative for medical students, physicians,
pharmacists, nurses, and general people.
So, keep reading to learn about ADME in pharmacokinetics –

2. What is meant by ADME in pharmacokinetics?
Pharmacokinetics is the branch of pharmacology (study of medicine) that deals
with how drugs move through the body.
If we split the term pharmacokinetics. In Greek, “Pharmakon” means drug (or
medicine), and “kinetics” implies movement.
In other words, pharmacokinetics is simply a movement of medicine in the body.
All medicines are indeed drugs, but not all drugs are medicines. So, medicine is
considered a drug.
The pharmacokinetics would be basically an ADME study. The ADME in
pharmacokinetics refers to absorption, distribution, metabolism, and excretion.

3. Every medicine must follow the ADME process (absorption, distribution,
metabolism, and excretion). Here, ADME in pharmacokinetics –
A represents absorption – medicine gets into the bloodstream.
D represents distribution – medicine moves from the bloodstream to tissue (or site
of action)
M represents metabolism – biotransformation of medicine (drug change from one
form to another form)
E represents excretion – medicine eliminate from the body via urine/stool
What are the 4 steps of pharmacokinetics?
For a good pharmacokinetic profile, a medicine must complete 4 steps of
pharmacokinetics in the human body, i.e., ADME.
Step 1 Absorption, Bioavailability & Prodrug
The first step of pharmacokinetics is absorption. A medicine can enter the body
either directly through blood or indirectly through GIT (stomach/intestine).
When you take medicine orally, it does not directly go to your bloodstream. Before
entering your main systemic circulation, medicine has to go through the liver via
hepatic portal vein.

4. Since liver generally receives all the blood by hepatic portal circulation that comes
from the stomach and intestine. So, before distribution, the medicine metabolizes
first in the liver. It is called First Pass Metabolism (FPM).

5. Some part of medicine gets broken down or metabolized before entering the
systemic circulation.
Due to this first pass metabolism, you lose some drugs during metabolism.
Whatever amount of medication you get in the systemic circulation represents
Bioavailability.
In other words, bioavailability means the amount (or percentage) of drug that
reaches the bloodstream. For example, if you take 100 mg of medicine and your
liver break 30 mg of the drug. You get only 70 mg of the absorbed drug into your
bloodstream. Here, bioavailability would be 70% of this drug.
The high first-pass metabolism has generally decreased the bioavailability of the
drug. Some examples of high first-pass metabolism drugs include Nitrates,
Testosterone, Lignocaine, Hydrocortisone, and Remdesivir.
Therefore, these drugs are never given orally.
Intravenous injection has 100 % bioavailability (get absorbed entirely) because it
directly goes to your blood and does not involve First Pass Metabolism.

6. Prodrug –
The liver makes most drugs inactive, but some drugs become active. These drugs
are called Prodrugs.
Generally, Prodrugs are not active initially but become active after First Pass
Metabolism. For example –
● All ACE inhibitors are prodrugs except captopril, and lisinopril like enalapril
(inactive) converts into enalaprilat (active form)
● All Proton Pump inhibitors are prodrugs like rabeprazole (inactive)
converted into sulphenamide (active form)
● Drugs for joints – Allopurinol (inactive) converts into oxypurinol (active
form), and azathioprine (inactive) converts into mercaptopurine (active
form)
● Steroids – Prednisone (inactive) converts into prednisolone (active)
● CNS agents – Levodopa (inactive) converts into dopamine (active form) and
methyldopa (inactive) converts into methyl-norepinephrine (active form)
Step 2 Distribution
The distribution step is only possible if the medicine successfully reaches the
bloodstream.

7. Once medicine reaches the blood, it has to distribute throughout your body, such as
the heart, brain, lungs, kidneys, etc.
Distribution describes how much medicine will reach tissues.

8. When medicine enters your blood, it interacts with various components of blood
like plasma protein (albumin and globulin).
It depends upon the affinity of drugs. Some drugs bind with plasma protein, and
some do not.
If a drug has high plasma protein binding, distribution will decrease, e.g., warfarin,
phenytoin, diazepam, etc. Conversely, unbound or free-form drugs (does not bind
to plasma protein) will have high distribution, e.g., gabapentin and pregabalin.
Another crucial pharmacokinetic parameter evaluates how much drug enters your
tissues, i.e., the volume of distribution.

9. A high volume of distribution means the maximum amount of drug distributed to
the tissues.
Conversely, a low volume of distribution means a minimum amount of drug
distributed to the tissues.
The volume of distribution is also a useful pharmacokinetic parameter for
calculating loading dose. Whereas clearance is a significant pharmacokinetic
parameter for calculating maintenance dose.
Step 3 Metabolism
Once the drug has done its action (therapeutic and undesirable effects), a medicine
has to clear out from the body. But it is difficult for the kidney to eliminate
lipophilic (or lipid soluble) drugs from the body.
So, medicine comes back into blood vessels from tissues.
After returning to the blood, medicine goes to the liver for biotransformation. Here,
lipid-soluble drugs (non-polar) convert into water-soluble (polar) drugs. This is
called the metabolism of a drug.

10. Thus, the primary purpose of metabolism is to make the medicine more polar (or
water-soluble) so that it cannot go back to your tissues. When a drug becomes
water soluble, it eliminates via urine or stool.

11. Step 4 Excretion
Once the drug becomes completely polar (or water-soluble), the drug reaches the
kidney. The kidney clears the water-soluble drug from the plasma via urine, called
renal excretion.
Some drugs are removed from the liver via bile, called non-renal excretion.
Examples include erythromycin, ampicillin, rifampicin, tetracycline, oral
contraceptives, vecuronium, and phenolphthalein.
Certain drugs which remove from the body by various routes of excretion –
● Lithium can remove via sweat, urine, saliva, and tear.
● Alcohol removes from the body via respiration
● Lactulose is directly eliminated from the stool.

12. Acidic medicines are more easily excreted in alkaline urine. While alkaline
medications are more easily excreted in acidic urine.
It makes the drug a more ionized compound, polar and water-soluble, so it can
dissolve in water and quickly be eliminated from the body.
ADME, pharmacokinetics pdf. Click here – absorption distribution metabolism and
excretion of drugs pdf
How does the liver metabolize the drugs exactly?
The liver has a vital role in drug metabolism. Your liver metabolizes the drug
through two types of reactions (Phase 1 and Phase 2) –
Phase I – Break the drug

13. The liver destroys the drug by introducing oxygen atoms by utilizing the CYP
enzyme so that it cannot re-enter your tissues.
CYP isoenzymes help in the metabolism of a drug. It decreases the therapeutic
effect and side effects of the drug.
There are six different P450 isozymes produced in the smooth endoplasmic
reticulum of the liver. It includes CYP1A2, CYP2C19, CYP2C9, CYP2D6,
CYP2E1, and CYP3A4.
Among these isoenzymes, CYP3A4 and CYP2D6 are the most important. Around
more than 50 % of drugs are metabolized by the CYP3A4 enzyme.
These enzymes destroy the drug through some reactions –
● Oxidation
● Reduction
● Hydrolysis
Phase II – Conjugation
After completion of Phase I, where drugs get break down or become inactive.
Then, the drug enters the Phase II reaction for conjugation.
Conjugation means attachment. Almost all drugs get conjugated in the liver, most
commonly with glucuronide. For example, bilirubin (lipid soluble) attaches with
glucuronide and converts into conjugated bilirubin. Conjugated bilirubin is water
soluble; it can eliminate from the body quickly.
Thus, the purpose of conjugation is to make the drug water soluble so that it can
eliminate quickly from urine.
There are some conjugation reactions mainly occur with –

14. ● Glucuronide
● Glutathione
● Glycine
● Methylation
● Acetylation
What is the different route of administration for
medication?

15. There are two main routes of administration for medicine – systemic and
non-systemic (Local)
I. Systemic (enter the blood) You can get the medicine in your body either directly
(via blood) or indirectly (via GIT).
Indirectly – enteral route
Enteral means something is passing through the intestine like oral and rectal.
Oral route: The oral route is the most common and convenient way to
administration of drugs, e.g., tablets, capsules, syrup, etc.
Rectal route: If you take a drug through the rectal, there is a possibility that 50%
drug can bypass the first pass metabolism and enter the blood, e.g., suppositories
Directly – parenteral route
Those medicines directly go to your blood, don’t touch the GIT (stomach or
intestine), and skip the first pass metabolism. These medicines are called Parenteral
drugs.
For example, intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c), etc.
Intravenous delivery gives complete absorption (or 100% bioavailability) of
medicine.
In life-threatening conditions, you generally need complete absorption of the drug
in the blood (100% bioavailability). Therefore, all emergency drugs are used for
intravenous delivery.
The inhalation route gives rapid and fastest absorption.
Sublingual administration also comes in the parenteral route. These medicines are
placed under the tongue, where they get absorbed and enter the bloodstream
directly, e.g., sorbitrate tablet (isosorbide dinitrate).
These medicines bypass the first pass metabolism.

16. II. Non-systemic (Local)
Medicines remain at the given site.
Topical
Whatever medicine you apply to your skin and the mucous membrane is called the
local route of administration. For example,
● Ointments and creams for skin
● Ear drops for ear
● Eye drops for eye
● Gargles, mouth paint, and mouth gel for the oral cavity
Deeper tissues
Some medicines are introduced into deeper tissue but do not enter your blood. For
example,
If you get an injection in your joints – Intra-articular
If you get an injection in your CSF – intra-thecal, e.g., spinal anesthesia
What are the factors affecting ADME of drugs?
There are a lot of crucial factors and parameters involved in every step of
pharmacokinetics –
Factors affecting absorption of drugs

17. 1. Chemical nature of drug
What will happen if you ingest hydrochloric acid (HCL)? It will burn your entire
mouth and esophagus.
A drug must be either weak acid or a weak base for good absorption. It readily
crosses the bilayer lipid membrane.
A weak acid drug (e.g., Aspirin) has good absorption in an acidic medium (e.g.,
stomach). The acidic drugs remain non-ionized (uncharged) in an acidic
environment, but it gets ionized (charged) in an alkaline medium (e.g., small
intestine).
Similarly, a weak base drug (e.g., Morphine) has good absorption in an alkaline
medium (e.g., small intestine). The weak base drugs remain non-ionized in an
alkaline environment, but it gets ionized in an acidic medium (e.g., stomach).
Therefore, most weak basic drugs are produced in enteric-coated tablets to prevent
the stomach’s acidic medium. These drugs go to your gut (or small intestine). Here,
it gets degrades and dissolves.
2. Lipid solubility
Lipid solubility is also an important factor in drug absorption.
Suppose the drug is lipophilic (lipid soluble). In that case, it will absorb well
because it can easily cross the lipid-rich cell membranes.
But, if the drug is hydrophilic (water soluble), it will be poor absorption because it
cannot cross the lipid-rich cell membranes.
Thus, a drug must be highly lipophilic (lipid soluble) for readily absorption.

18. 3. Pharmaceutical factors
Pharmaceutical factors have a more significant effect on the rate of absorption.
a. Drug formulation – Liquid dose preparation (like syrup or suspension) is better
absorbed in the bloodstream than solid dose preparation (e.g., tablet)
b. Excipients – Absorption also depends on the type of excipients used in drug
formulation. For example, a Hard binder with the drug is difficult to break into
GIT. While light binder with the drug may get quickly break into GIT.
4. Surface area available for absorption
The absorption of medicine will increase if there is a large surface area.
Surface area is directly proportional (∝) to absorption of the drug
More surface area ∝ Increase absorption of the drug
For example, the small intestine has 1000-fold compared to the stomach. These
folds increase the surface area of the intestine. So, the drug will be more efficiently
absorbed in the small intestine area.
5. Presence of foods
Drug food interaction also interferes with absorption.
● You can take certain medicines with the meal because it enhances
absorption, e.g., Albendazole with a fatty meal.

19. ● You should not take some medicines with the meal because it retards the
absorption of the medicine, e.g., Proton pump inhibitors (Rabeprazole), ACE
inhibitors that work better on an empty stomach, Levothyroxine, etc.
6. Diseases
As per a study, it is also possible for gastrointestinal disorders (such as coeliac,
peptic ulcers, and inflammatory bowel diseases) to slow gastric emptying and
delay the full absorption of medications like cyclosporin, benzodiazepines,
anticonvulsants, amitriptyline, and paracetamol.
In case of diarrhea, absorption of the drug will decrease. But in constipation,
absorption of the drug will increase.
Factors affecting the distribution of drugs
1. Blood flow
Medicines are more likely to be distributed to those organs that receive high blood
flow, e.g., the brain, heart, liver, and kidney.
Poor blood flow in skeletal muscles like legs and arms. So, medicines will reach
delay in these body parts.
2. Penetration of capillaries
Distribution depends on capillary structures like high permeability and low
permeability.

20. It is easier to distribute medicines in highly perfused (penetrated) organs such as
the heart, liver, and kidney. In these organs, endothelial cells have a slit junction
where medications easily cross the membrane.
But some anatomical barriers are found in specific organs, e.g., the blood-brain
barrier (BBB). In BBB, there is a tight junction of endothelial cells. Due to this,
water-soluble medicine cannot easily cross the membrane.
Only high lipid-soluble drugs can penetrate BBB and enter the brain. For example
– Dopamine is a water-soluble drug, so it can’t cross BBB. But when you take
Levodopa (L-dopamine), it is a lipid-soluble drug that can cross BBB easily.
Another barrier in pregnancy is found to save your baby from harmful substances,
i.e., the blood placental barrier (BPB).
3. Plasma protein binding
Several proteins (such as albumin and globulin) are suspended in our blood. When
a medicine enters our blood circulation, some drugs bind to these proteins and
make a macro-molecule complex.
Usually, acidic drugs bind with albumin, and basic drugs bind with globulin. But
the primary protein involved in drug binding is plasma albumin. It acts as a
reservoir.
Drug + plasma protein = Protein Drug Complex (stay long time in body)
Drug-plasma protein complexes decrease the drug’s distribution in various organs
or tissues because the drug is slowly released from this complex.
High Plasma Protein Binding (PPB) drugs –
Certain drugs have very high plasma protein bindings, e.g., Warfarin (99%),
Phenytoin, Sodium Valproate, Tiagabine, Diazepam, Tolbutamide, Sulphonamides,
etc.

21. High plasma protein drugs are long-acting drugs that increase half-life due to the
slow release of drugs from protein complexes.
The high PPB drugs are less free form and produce less therapeutic action. That’s
why you need to take a higher dose. These drugs are difficult to remove from the
body.
The high PPB drugs may displace other drugs and increase their toxicity. For
example, if you have been on warfarin for a long time and start taking
sulphonamide medicine.
Then this sulphonamide may remove the warfarin from the plasma protein binding
place. Due to this displacement, warfarin gets free (unbound) in your blood. This
unbound warfarin can bind to tissue and increases the effect of warfarin that causes
warfarin toxicity.
Free form (unbound drug)-
Not all drugs bind to plasma protein; it depends on the drug’s affinity. If
medications are unbound, they may be freely circulated in the blood. The unbound
drug (or free drug) is rapidly distributed into various organs or tissues.
Unbound drug (free drug) – more efficiently distributed throughout the body
4. Volume of distribution
The volume of distribution (Vd) is also an essential pharmacokinetic parameter.
Volume of distribution means medicine leaves the blood plasma and enters the
organs or tissues.
Here, we can determine how much drug binding to tissue protein by a simple
formula –
Volume of distribution (Vd) = amount of drug distributed into tissue (mg) /drug
concentration in blood plasma (mg/L)

22. The volume of distribution is (∝) directly proportional to the amount of drug
distributed into tissue.
In other words, the volume of distribution will be high if the total amount of drug
is distributed through your body tissues. A high volume of distribution also
increases the half-life of the drug.
For example, Chloroquine has 15000 L Vd, and its half-life is around 1 to 2
months.
Conversely, the volume of distribution will decrease if drug concentration is more
in the circulatory system (or bloodstream).
Vd is inversely proportional (1/ ∝) to drug concentration in blood plasma
For example,
High plasma protein binding drugs (like warfarin) have a low volume of
distribution of 0.15 L/kg because it slowly releases from the protein binding
complex.
Another factor influences the volume of distribution, i.e., Lipid insolubility. Lipid
insoluble drugs (like streptomycin and gentamicin) have a low Vd (0.25 L/kg)
because these drugs do not cross easily to the lipid-rich cell membrane.
5. Loading and maintenance dose
The loading dose of the drug depends on the volume of distribution. If the Vd is
high, you should take more loading doses to achieve plasma concentration.
Conversely, if the Vd is low, you need to decrease the drug loading dose to achieve
plasma concentration.
The drug is generally removed from the body by Clearance (CL). High clearance
means the drug gets rapidly removed from the body.

23. To keep the drug concentration the same, you must add more. So, the maintenance
dose depends on (CL).
Factors affecting metabolism of drugs
Certain drugs are potent enzyme inducers or enzyme inhibitors. These drugs
influence the drug plasma concentration –
Factors affecting excretion of drugs
Some essential factors (or pharmacokinetic parameters) contribute to the
elimination of drugs –

24. 1. Half-life
It is important to remember that different drugs have different half-lives.
Half-life means the time taken for the drug to become 50% original.
Suppose you take 100 mg of medicine, and its half-life is 4 hours. Then, every 4
hours, 50 % drug will eliminate from your body. For example,
0 hour = 100 mg drug (100%)
↓
4 hours = 50 mg drug (50%)
↓
8 hours = 25 mg drug (25%)
↓
12 hours = 12.5 mg drug (12.5%)
↓
16 hours = 6.25 mg drug (6.25%)
↓
20 hours = 3.125 mg drug (3.125%)
↓
24 hours = 1.562 mg drug (1.562%)
↓
28 hours = 0.781 mg drug (0.781%)

25. It will take around 28 hours to clear from your body if the drug’s half-life is 4
hours.
If the drug’s half-life is more, it will stay more time in your body, which may cause
toxicity.
Half-life is a useful pharmacokinetic parameter to decide the timing of drug dose.
For example,
● You should take medicine twice daily if a drug’s half-life is 12 hours.
● If a drug’s half-life is 8 hours, you should take the medication thrice a day.
● If a drug’s half-life is 6 hours, you should take medicine four times a day.
2. Elimination rate
Elimination rate (ER) means the amount of drug eliminated per unit time, e.g., a
drug eliminated at the rate of 25 mg/hour.
Drugs remove from your body either first-order kinetic or zero-order kinetic.

26. Conclusion

27. We have discussed the complete process of ADME in pharmacokinetics. We
learned various pharmacokinetic parameters like –
● Bioavailability of drug
● First pass metabolism
● Prodrug
● Plasma protein binding of drugs
● Volume of distribution
● Phase I and Phase II metabolic reactions
● Enzyme inducers and enzyme inhibitors
● Half-life of drug
● Elimination rate (zero-order and first-order kinetics)
These parameters of ADME in pharmacokinetics help scientists (or drug
developers) in the development of an ideal drug.
The study of ADME in pharmacokinetics also helps in dose calculation, the timing
of drug, drug-drug interactions, drug-food interactions, etc.
Thus, understanding the pharmacokinetic mechanisms is essential to start the safest
and most effective treatment regimens for patients.
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28. FAQ
Q 1 Why is ADME important?
The pharmacokinetic study provides the essential clinical parameters of the drug.
ADME reflects what your body does to the drug. It is required to determine dose
calculation, drug timing, loading dose, maintenance dose, drug discovery, and
development process.
Q 2 Why metabolism of drugs essential?
The primary purpose of the metabolism of drugs is to make the drug more polar (or
water-soluble) so that it can eliminate quickly from the kidney via urine.
Q 3 How does drug distribution work in the body?
The distribution of drug depends upon the degree of plasma protein and volume of
distribution like –
High plasma protein drug → less distribution
A high volume of distribution → more distribution
Q 4 What are the basic drug transport mechanisms?
There are 2 broad ways to transport medicine to cross a membrane and enter the
bloodstream.
● Passive transport mechanism – No ATP (energy) required
● Active transport mechanism – ATP (energy) required

29. In Passive transport, drugs reach into the blood via two mechanisms – Simple
Passive diffusion and Facilitated diffusion.
While in active transport, the drug is absorbed via two mechanisms – Active
transport and Pinocytosis.
Sources –
1. Michelle A. Clark et al. Lippincott’s Illustrated reviews: Pharmacology, 5th
edition. Wolters Kluwer health, 2012, Principles of drug therapy, Unit-1, Pages 1 to
24.
2. KD Tripathi. Essentials of medical pharmacology, 7th edition. Jay Pee Brothers,
2013; General pharmacological principles; Chapter 1- 3, Pages 1 to 36.