ADME

ADME  is an abbreviation in pharmacokinetics and pharmacology for

"absorption, distribution, metabolism, and excretion", and describes the disposition
of a pharmaceutical compound within an organism. The four criteria all influence
the drug levels and kinetics of drug exposure to the tissues and hence influence the
performance and pharmacological activity of the compound as a drug.

Sometimes, liberation and/or toxicity are also considered, yielding LADME, ADMET,

or LADMET.

Components:

1) Absorption/administration

For a compound to reach a tissue, it usually must be taken into the bloodstream -

often via mucous surfaces like the digestive tract (intestinal absorption) - before
being taken up by the target cells. Factors such as poor compound solubility, gastric
emptying time, intestinal transit time, chemical instability in the stomach, and
inability to permeate the intestinal wall can all reduce the extent to which a drug is
absorbed after oral administration. Absorption critically determines the
compound's bioavailability. Drugs that absorb poorly when taken orally must be
administered in some less desirable way, like intravenously or
by inhalation (e.g. zanamivir). Routes of administration are an important
consideration.

2) Distribution

The compound needs to be carried to its effector site, most often via the
bloodstream. From there, the compound may distribute into muscle and organs,
usually to differing extents. After entry into the systemic circulation, either
by intravascular injection or by absorption from any of the various extracellular
sites, the drug is subjected to numerous distribution processes that tend to lower its
plasma concentration.

Distribution is defined as the reversible transfer of a drug between

one compartment to another. Some factors affecting drug distribution include
regional blood flow rates, molecular size, polarity and binding to serum proteins,
forming a complex. Distribution can be a serious problem at some natural barriers
like the blood–brain barrier.

3) Metabolism

Compounds begin to break down as soon as they enter the body. The majority of
small-molecule drug metabolism is carried out in the liver by redox enzymes,
termed cytochrome P450 enzymes. As metabolism occurs, the initial (parent)
compound is converted to new compounds called metabolites. When metabolites
are pharmacologically inert, metabolism deactivates the administered dose of
parent drug and this usually reduces the effects on the body. Metabolites may also
be pharmacologically active, sometimes more so than the parent drug (see prodrug).

4) Excretion

Compounds and their metabolites need to be removed from the body via excretion,

usually through the kidneys (urine) or in the feces. Unless excretion is complete,
accumulation of foreign substances can adversely affect normal metabolism.
There are three main sites where drug excretion occurs. The kidney is the most
important site and it is where products are excreted through urine. Biliary excretion
or fecal excretion is the process that initiates in the liver and passes through to the
gut until the products are finally excreted along with waste products or feces. The
last main method of excretion is through the lungs (e.g. anesthetic gases).
Excretion of drugs by the kidney involves 3 main mechanisms:

 Glomerular filtration of unbound drug.

 Active secretion of drug by transporters or cations such as choline,
histamine
 Filtrate 100-fold concentrated in tubules for a favorable concentration
gradient so that it may be secreted by passive diffusion and passed out through
the urine.

Toxicity:

-Sometimes, the potential or real toxicity of the compound is taken into account

(ADME-Tox or ADMET). Parameters used to characterize toxicity include the
median lethal dose (LD50) and therapeutic index.

-Computational chemists try to predict the ADME-Tox qualities of compounds

through methods like QSPR or QSAR.

-The route of administration critically influences ADME.

The Role of ADME & Toxicology Studies in Drug Discovery &

Development

What do ADMET studies provide to drug developers?

A critical piece in drug discovery and development is conducting DMPK (Drug

Metabolism and Pharmacokinetics) studies, often referred to as ADMET
(Absorption, Distribution, Metabolism, Elimination, Toxicity) studies. These studies
help to determine the viability of a drug candidate by answering these key
questions:
 Absorption – How much of the drug is absorbed and how quickly?
(bioavailability)

 Distribution- Where is the drug distributed within the body? What is

the rate and extent of the distribution?

 Metabolism- How fast is the drug metabolized? What is the mechanism

of action? What metabolite is formed and is it active or toxic?

 Elimination- How is the drug excreted and how quickly?

 Toxicity-Does this drug have a toxic effect to body systems or organs?

It is estimated that close to 50% of drug candidates fail because of unacceptable

efficacy1 and that up to 40% of drug candidates have failed in the past due to
toxicity2. Drugs such as mibefradil, soruvidine, and phenylpropanolamine
hydrochloride have been pulled off the market due to drug-drug interactions or
toxicity3. It has become obvious to both regulators and drug makers that in addition
to pharmacological properties, ADME/Tox studies play a crucial role in the success
of a drug candidate. Due to this impact on eventual success, these studies now occur
early in the drug discovery process.

In vitro and in vivo studies are conducted to enable a drug developer to make a go-

no-go decision regarding if a drug should be selected as a drug candidate, and
moved into late-stage preclinical and clinical programs. ADME properties allow drug
developers to understand the safety and efficacy of a drug candidate, and are
necessary for regulatory approval.

The Food and Drug Administration (FDA) has produced several guidance
documents for industry such as Safety Testing of Drug Metabolites, In Vitro
Metabolism and Transporter-Mediated Drug-Drug Interactions Studies, Clinical
Drug Interaction Studies — Study Design, Data Analysis, and Title 21 part 58 Good
Laboratory Practices for Nonclinical Laboratory Studies to provide instruction and
to ensure that best practices are employed when evaluating the safety and efficacy
of a drug candidate. The underlying goal and end-game for all ADME/Tox studies is
to better understand a compound’s metabolite-mediated toxicity and safety profile
to make a concrete decision on whether the compound can progress to late stage
preclinical and clinical studies to enable filing for an Investigational New Drug
(IND), New Drug Application (NDA), or a Biologics Licensing Application (BLA).

To help streamline data handling and data processing in research

laboratories, ADME/Tox capabilities have been developed for use with Thermo
Fisher™ Platform for Science™ software. These capabilities provide a mechanism for
laboratories to manage assay protocols, track reagents and materials, capture assay
data, and calculate results.
Heavy Metal Poisoning

What is heavy metal poisoning? 

Heavy metals are are elements that are naturally found in the earth. They’re used in
many modern-day applications, such as agriculture, medicine, and industry.

Your body even naturally contains some. Zinc, iron, and copper, for example, are
necessary for regular body function, as long as they aren’t present in toxic amounts.
Heavy metal poisoning occurs when your body’s soft tissues absorb too much of a
particular metal.

The most common metals that the human body can absorb in toxic amounts are:

 mercury
 lead
 cadmium
 arsenic
You might be exposed to high concentrations of these metals from food, air or water
pollution, as well as medicine, food containers with improper coating, industrial
exposure, or lead-based paint.
What are the symptoms of heavy metal poisoning? 

The symptoms of heavy metal poisoning vary, depending on the type of metal
involved.

General symptoms

Common symptoms across several types of heavy metal poisoning include:

 diarrhea
 nausea
 abdominal pain
 vomiting
 shortness of breath
 tingling in your hands and feet
 chills
 weakness

Children with heavy metal poisoning may have unusually formed or weakened
bones. Pregnant people may also have a miscarriage or deliver prematurely.

Metal-specific symptoms

Certain types of heavy metal poisoning can cause additional symptoms. Here’s a
look at the symptoms linked to some of the most common types.

1) Mercury poisoning symptoms:

 lack of coordination
 muscle weakness
 hearing and speech difficulties
 nerve damage in your hands and face
 vision changes
 trouble walking

2) Lead poisoning symptoms:

 constipation
 aggressive behavior
 sleep problems
  irritability
 high blood pressure
 loss of appetite
 anemia
 headaches
 fatigue
 memory loss
 loss of developmental skills in children

3) Arsenic poisoning symptoms:

 nausea, vomiting, and diarrhea

 red or swollen skin
 spots on your skin, such as warts or lesions
 unusual heart rhythm
 muscle cramps

4) Cadmium poisoning symptoms:

 fever
 breathing problems
 muscle pain

What causes heavy metal poisoning?

Heavy metals can enter your body in different ways. You might consume them in the
food you eat or absorb them through your skin, for example.

Here’s how you might be exposed to various heavy metals. Keep in mind that heavy
metal poisoning occurs with heavy or frequent exposure, usually over a long period
of time. Occasional exposure won’t lead to heavy metal poisoning.

1) Arsenic

 working near a hazardous waste site

 living in an area that has high levels in rocks, water, and soil
 ingesting insecticides, pesticides, or herbicides
 eating contaminated seafood or algae
 drinking contaminated water

2) Cadmium
  working in an industrial setting, especially one where ore is processed
or smelted

 welding on alloys that contain cadmium or using silver solders

 inhaling cigarette smoke
3) Lead

 living in a home with high levels of lead-based paint

 doing industrial construction work, radiator repair, or smelter
operations

 being in firing ranges

 using kohl cosmetics

 applying progressive hair dyes, though the U.S. Food and Drug

AdministrationTrusted Source (FDA) is working to change this using foreign
digestive remedies, calcium products, kohl, surma, kajal, or progressive hair
dyes

4) Mercury

 mining, producing, or transporting mercury

 mining and refining gold and silver ores
 consuming contaminated fish or water
 manufacturing mirrors, X-ray machines, or vacuum pumps

While anyone can develop heavy metal poisoning, children are more vulnerable to
it, particularly lead poisoning. Older homes sometimes contain lead paint. If a child
touches a wall with lead paint before touching their mouth, for example, they may
be exposed. This can lead to brain damage, since their brains are still developing.

Still, according to the National Organization for Rare Disorders, the number of

children with signs of potentially harmful lead levels has dropped by 85 percent
over the last 20 years.

How do I know if I have heavy metal poisoning? 

Doctors can usually check for heavy metal poisoning with a simple blood test known
as a heavy metals panel or heavy metal toxicity test.

To do the test, they’ll take a small blood sample and test it for signs of heavy metals.
If you have symptoms of heavy metal poisoning, but your blood test only shows low
levels, you doctor might do some additional testing.
These may include:

 kidney function tests

 liver function studies
 urine analysis
 hair analysis
 fingernail analysis
 electroardiograms
 X-rays

Heavy Metal Poisoning Treatment

Your doctor may recommend a urine or blood test to find out if you have heavy
metal poisoning.

If the test shows that you do have heavy metal poisoning, the first step of treatment
is to eliminate the exposure.

Other forms of treatment may include:

 Chelating agents such as Chemet (succimer), which bind to the metal

and are then excreted in your urine

 Suctioning of the stomach to remove some ingested metals

 A diuretic called mannitol (Aridol, Osmitrol), corticosteroid drugs, or

intracranial monitoring for swelling of the brain

 Hemodialysis and/or other special treatments if kidney failure occurs

Heavy Metal Poisoning Prevention

The following tips may help you prevent heavy metal poisoning:

 Wear masks and protective clothing if you work around heavy metals

 Since many metals accumulate in dust and dirt, keep these out of your
home as much as possible

 Pay attention to local fish advisories regarding mercury levels

 Be aware of potential sources of lead exposure.

References:

 https://www.healthline.com/health/heavy-metal-poisoning

 https://www.everydayhealth.com/heavy-metal-poisoning/guide/

 Kennedy, Tony. “Managing the Drug Discovery/Development

Interface.” Drug Discovery Today, vol. 2, no. 10, 1997, pp. 436–444.,
doi:10.1016/s1359-6446(97)01099-4.

 DiMasi, J A. “Success Rates Fir New Drugs Entering Clinical Testing in

the United States.”Clinical Pharmacology & Therapeutics, 58, no. 1, July 1995,
doi:10.1016/0009-9236(95)90066-7 .

 Li, Albert P. “Screening for Human ADME/Tox Drug Properties in Drug

Discovery.” Drug Discovery Today, 6, no. 7, 2001, pp. 357–366.,
doi:10.1016/s1359-6446(01)01712-3.

 Wan, Hong. “What ADME Tests Should Be Conducted for Preclinical

Studies?” Admet & Dmpk, 1, no. 3, 2013, doi:10.5599/admet.1.3.9.
 

 S.K. Balani; V.S.Devishree; G.T. Miwa; L.S. Gan; J.T. Wu; F.W. Lee (2005).
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 Singh S.S. (2006). "Preclinical pharmacokinetics: an approach towards

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 Tetko IV, Bruneau P, Mewes HW, Rohrer DC, Poda GI (2006). "Can we

estimate the accuracy of ADME-Tox predictions?," (pre-print). Drug Discov
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