describes the phenomenon of first pass metabolism, its significance in pharmacology etc in details

1. Detoxification-2
Dr. Radhakrishna G Pillai
MSc, Bed, PhD, LLB, MSc (Bioinfo-London), PGCE, SLTP, PGDDE

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

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

8. Drug metabolism

9. Antiporter-First pass metabolism

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

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