First pass metabolism

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

6. 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

7. Drug metabolism

8. Antiporter -First pass metabolism

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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