Factors affecting ADME

ADME
Absorption
Distribution
Metabolism
elemination
Absorption affecting factors
 Drug absorption is a pharmacokinetic parameter that refers to the way a drug is
absorbed from a pharmaceutical formulation into the bloodstream
Effect of pH on drug absorption
Most drugs are either weak acids or weak bases
Acidic drugs (HA) release a proton (H+), causing a charged anion (A−)
Weak bases (BH+) can also release an H+. However, the protonated form of basic
drugs is usually charged, and loss of a proton produces the uncharged base (B)
Drug passes through membranes more readily if it is uncharged
Protonated HA can permeate through membranes, and A− cannot
The uncharged form B penetrates through the cell membrane, but the protonated
form BH+ does not
/ the strength of the weak acid or base is represented by the ionization constant,
pK
[: The lower the pKa of a drug, the more acidic it is
, : the higher the pKa , the more basic is the drug
Blood flow to the absorption site:
The intestines receive much more blood flow than the stomach, so absorption
from the intestine is favored over the stomach
Total surface area available for absorption:
With a surface rich in brush borders containing microvilli, the intestine has a
surface area about 1000-fold that of the stomach, making absorption of the drug
across the intestine more efficien
Contact time at the absorption surface
: If a drug moves through the GI tract very quickly, as can happen with severe
diarrhea, it is not well absorbed. Conversely, anything that delays the transport
of the drug from the stomach to the intestine delays the rate of absorption of the
drug.
The presence of food in the stomach both dilutes the drug and slows gastric
emptying. Therefore, a drug taken with a meal is generally absorbed more slowly
 Expression of P-glycoprotein
 : P-glycoprotein is a transmembrane transporter protein responsible for
transporting various molecules, including drugs, across cell membranes It is
expressed in tissues throughout the body, including the liver, kidneys,
placenta, intestines, and brain capillaries, and is involved in transportation of
drugs from tissues to blood. That is, it “pumps” drugs out of the cells. Thus,
in areas of high expression, P-glycoprotein reduces drug absorption. In
addition to transporting many drugs out of cells, it is also associated with
multidrug resistance.
Distribution affecting factor
 Drug distribution
 is the process by which a drug reversibly leaves the bloodstream and enters the
interstitium (extracellular fluid)
 Factors affecting distribution
 Blood flow
 The rate of blood flow to the tissue capillaries varies widely. For instance, blood
flow to the “vessel-rich organs” (brain, liver, and kidney) is greater than that to the
skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood
flow. Variation in blood f low partly explains the short duration of hypnosis
produced by an IV bolus of propofol (). High blood flow, together with high
lipophilicity of propofol, permits rapid distribution into the CNS and produces
anesthesia. A subsequent slower distribution to skeletal muscle and adipose tissue
lowers the plasma concentration so that the drug diffuses out of the CNS, down the
concentration gradient, and consciousness is regained.
 Capillary permeability
 Capillary permeability is determined by capillary structure and by the chemical
nature of the drug. Capillary structure varies in terms of the fraction of the
basement membrane exposed by slit junctions between endothelial cells. In the
liver and spleen, a significant portion of the basement membrane is exposed due
to large, discontinuous capillaries through which large plasma proteins can pass .
In the brain, the capillary structure is continuous, and there are no slit junctions .
To enter the brain, drugs must pass through the endothelial cells of the CNS
capillaries or be actively transported. For example, a specific transporter carries
levodopa into the brain. By contrast, lipid-soluble drugs readily penetrate the CNS
because they dissolve in the endothelial cell membrane. Ionized or polar drugs
generally fail to enter the CNS because they cannot pass through the endothelial
cells that have no slit junction( These closely juxtaposed cells form tight
junctions that constitute the blood–brain barrier.
 Binding to plasma proteins:
 Reversible binding to plasma proteins sequesters drugs in a nondiffusible
form and slows their transfer out of the vascular compartment. Albumin is the
major drug-binding protein and may act as a drug reservoir (as the
concentration of free drug decreases due to elimination, the bound drug
dissociates from the protein). This maintains the freedrug concentration as a
constant fraction of the total drug in the plasma.
 Binding to tissue proteins:
 Many drugs accumulate in tissues, leading to higher concentrations in tissues
than in the extracellular fluid and blood. Drugs may accumulate as a result of
bindingto lipids, proteins, or nucleic acids. Drugs may also be actively
transported into tissues. Tissue reservoirs may serve as a major source of the
drug and prolong its actions or cause local drug toxicity. (For example,
acrolein, the metabolite of cyclophosphamide, can cause hemorrhagic cystitis
because it accumulates in the bladder.
 Lipophilicity
 The chemical nature of a drug strongly influences its ability to cross cell
membranes. Lipophilic drugs readily move across most biologic membranes.
These drugs dissolve in the lipid membranes and penetrate the entire cell
surface. The major factor influencing the distribution of lipophilic drugs is
blood flow to the area. In contrast, hydrophilic drugs do not readily penetrate
cell membranes and must pass through slit junctions.
Metabolism affecting factors
 Chemical factors
 Enzyme indication
 Example
 You shouldn’t take rifampicin with oral contraceptives
because rifampicin is considered as cyp3A4 inducer , so
it decreases the effectiveness of oral contraceptives
 Enzyme inhibition
 Enzyme inhibition is decrease in drug metabolizing
ability of enzyme
 Example
 Terfenadine, used for allergy, is contraindicated with
erythromycin because that erythromycin is considered
as cyp3A4 inhibitor, so it decrease metabolizing
ability of enzyme that is responsible for metabolizing
terfenadine then it may cause prolongation in QT
interval in overdose and produce fatal ventricular
arrhythmias
 Biological factors
Elemination affecting factors
 Polarity
 Drugs must be sufficiently polar to be eliminated from the body.
Removal of drugs from the body occurs via a number of routes,
the most important being elimination through the kidney into
the urine. Patients with renal dysfunction may be unable to
excrete drugs and are at risk for drug accumulation and adverse
effects.
 Pka
 Inverse relationship between the acidity and the rate of renal
excretion
 The more acidic analogs were rapidly excreted in man under the
normal circumstances of acid urine.the less acidic analogs were
very slowly excreted