2. Phase III transporters
• After Phase II the transformed substances need to be
transported out of the cell
• This happens during Phase III
• This is a vital function in the detoxification process
• Accomplished by the efflux transporters or efflux pumps
• The same efflux pumps involved in the antiporter
mechanism
• Therefore, efflux transporters / efflux pumps serve a dual
function with the Phase III
3. Efflux Transporters
– Efflux transporters act by eliminating both
endogenous and exogenous Phase II conjugated
metabolites from hepatocytes and other tissues
– Antiporter action –nature’s gatekeeper for cellular
entry by eliminating unwanted compounds before
biotransformation
– More than 350 unique human transporters have been
identified
4. Efflux transporters
– The best known and most studied transporter is the P-
glycoprotein
• Apical membrane transporter
• Expressed in intestinal mucosal membrane, proximal tubule
epithelium, liver cells, luminal blood-brain barrier, placenta etc.
5. Efflux Transporters
• Lipophilic substances are the substrate
•They are substrates specific
• Efflux transporters can also be induced:
• increasing the transporter activity and
• Can be inhibited :
•causing substrate levels to become higher
6.
7. Antiporter & First pass metabolism
– Antiporters allows more opportunities for Phase I activity
to metabolize unwanted chemicals before they are taken
into circulation
– Antiporters are important factor in the first pass
metabolism of pharmaceuticals and other xenobiotics
– FP is the biotransformation of unwanted compounds by
intestinal enzymes and the liver before the compound
reaches systemic circulation
– This results in lower systemic bioavailability of a parent
compound, which is an important effect when
pharmaceuticals are involved
10. First pass metabolism
• The first pass effect is a phenomenon in which a drug gets
metabolized
• At a specific location in the body
• That results in a reduced concentration of the active drug
upon reaching its site of action or the systemic circulation
• Often associated with the liver, as this is a major site of drug
metabolism
• FP effect can also occur in the lungs, vasculature, GI tract,
and other metabolically active tissues in the body
11.
12. First Pass effect
• Various factors augment FP effect;
– such as plasma protein concentrations, enzymatic activity, and
gastrointestinal motility
• The extent varies from patient to patient
• Noted differences in the first pass effect based on gender
and age
• This must also be taken into consideration when
determining appropriate dosing
• If the first-pass effect is prominent in a patient,
– require administration via different route to bypass the first-
pass effect
13. Clinical significance
• FP effect is crucial in the proper administration and maintenance of
pharmacological therapy
• Some drugs that undergo considerable first-pass metabolism
include
– alprenolol, 5-fluorouracil, morphine, pentazocine, and mercaptopurine
• When given orally, these drugs are quickly metabolized via the first-
pass effect
• Requiring their oral dosages to be much larger than their
intravenous dosages
• The first pass effect also has an impact on peak drug concentrations
• which may result in drug concentration peaks occurring much
earlier than they would in a parenteral dose
14. De-Conjugation
• Unwanted compounds after the biotransformation process is
eliminated from the cell through urine or the bile
• Conjugated compounds released into the bile, may be
subjected to the action of hydrolytic enzymes
• Hydrolytic enzymes originate from some types of intestinal
microflora (bacterial microorganisms), which varies from
person to person
• One of the functions of these intestinal microflora enzymes
twist the whole detoxification process by de-conjugating
some of the biotransformed compounds
• De-conjugation results in an increase in lipophilic compounds
and renders them once again subject to passive uptake
15. De-conjugation
• Re-absorbed compounds enter the circulation via the
hepatic portal vein, which shunts the compound back
to the liver where the compound can, once again, go
through the biotransformation process
• This process is called entero-hepatic circulation (EHC)
• A compound may undergo several cycles of EHC
resulting in a significant increase in the retention time
of a compound in the body and increased toxicity
16. • An example of de-conjugation is:
– Glucuronidation can be reversed (de-conjugated)
by an enzyme called beta-glucuronidase
– Beta-glucuronidase is found in the intestines and
is produced by pathological bacteria
– Calcium d-glucarate, a natural substance found in
certain vegetables and fruits can inhibit beta-
glucuronidase activity resulting in the proper
elimination of conjugated toxins
17. • Enzymes are extensively used in the
transformation of toxins
• There is a homeostatic arrangements between
phase I and Phase II reactions
• Phase III make use of transporter proteins
instead of enzymes used in the other two
phases
Hinweis der Redaktion
The part of the cell membrane at the apical end of the cell, which faces the outside or the lumen of the cavity
