Question
Asked 30th Apr, 2015

Can someone provide a simple explanation for the 1st pass effect?

its a phenonmenon of the drug as the changing of its conc. in the path undirectly of the systemic circulation 

Most recent answer

9th Nov, 2020
Robin Whelpton
Queen Mary, University of London
Phase 1 and phase 2 refer to the KINDS of metabolism. Phase 1 reactions usually add or reveal reactive groups. For example hydroxylation of diazepam to temazepam. Phase 1 reactions are often oxidations or hydrolysis reactions, although reductions also occur. In terms of first-pass metabolism in the liver - hydrolysis of pharmacologically inactive esters (prodrugs) to active drugs are important phase 1 reactions. Phase 2 reactions are conjugation reactions where an other molecule is added, for example glucuronic acid to form a glucuronide. Morphine has -OH groups that can be glucuronidated directly and this would be an example of first-pass metabolism when it occurs in the liver before morphine reaches the systemic circulation. Temazepam can form a glucuronide directly. Phase 2 metabolites are generally readily exceted but not always and can be toxic.
Let me push our book - Introduction to Drug Disposition and Pharmacokinetics, SH Curry & R Whelpton. Get your library to get you access.

Popular answers (1)

4th May, 2015
Paul Dessauer
Peer Based Harm Reduction WA (formerly WASUA)
As Phillipe has explained, a drug taken orally is absorbed through the intestinal mucosa and transported to the liver before entering the systemic bloodstream and flowing to the brain and other organs.
Further to Phillipe's comments, it is largely enzymes in the liver that break down the drug. Avoiding first-pass metabolism allows a much larger proportion of the dose to reach the brain or other organs.
Oral consumption is much less efficient than rectal, vaginal, buccal, sublingual or insufflation (snorting through the nose) routes of administration. This is because when a drug is administered by these routes it is absorbed across mucus membranes (respectively; in the anus, vagina, cheek, under the tongue, or up the nose) and passes directly into the systemic blood stream, traveling straight to the brain and other organs without "first pass" liver metabolism taking place.
Smoking or vaporizing a drug allows the substance to be absorbed directly into the systemic bloodstream across the lining of the lungs, and so is even more immediate in effect and more efficient than any of the above routes. 
Finally, injecting a drug is even more immediate and efficient than smoking/vaporizing and inhaling. Subcutaneous injection is slightly less immediate than intramuscular injection, which is slightly less immediate than intravenous administration.
Some medications are 'pro-drugs'. They have little or no effect, but some of their metabolites are active drugs. The classic example is codeine, which has no real analgesic effect but is metabolised by the liver into morphine. A similar example is tramadol, which has little analgesic effect but is metabolised in the liver to O-desmethyltramadol and other active metabolites. Lysdexamfetamine has no effect, but is broken down by enzymes in red blood cells to form L-lysine, (a naturally occurring essential amino acid), and dexamphetamine. Avoiding first-pass liver metabolism conveys no advantage of immediacy or efficiency with pro-drugs.
With most psychoactive substances, first pass liver metabolism can make a very significant difference in the amount of the drug that ends up reaching the brain and other organs. When a patient is maintained on IV morphine in a hospital, and is then discharged into the community, they are typically transferred onto oral morphine pills. If the Doctor wants to provide enough oral morphine to ensure the same level of pain relief as the patient is receiving IV, they will typically increase the dose in mg threefold.
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All Answers (5)

1st May, 2015
Philippe Berny
Vetagro Sup, France, Marcy l'étoile
Alter absorption in the intestine, all nutrients and drugs go through the liver via the local blood vessels. Based on their size, lipophilic nature, some will be retained in the liver and only partially reach the systemic blood stream (lipophilic substances are usually more taken up). This first pass effect can explain limited bioavailability after oral administration.
3 Recommendations
4th May, 2015
Paul Dessauer
Peer Based Harm Reduction WA (formerly WASUA)
As Phillipe has explained, a drug taken orally is absorbed through the intestinal mucosa and transported to the liver before entering the systemic bloodstream and flowing to the brain and other organs.
Further to Phillipe's comments, it is largely enzymes in the liver that break down the drug. Avoiding first-pass metabolism allows a much larger proportion of the dose to reach the brain or other organs.
Oral consumption is much less efficient than rectal, vaginal, buccal, sublingual or insufflation (snorting through the nose) routes of administration. This is because when a drug is administered by these routes it is absorbed across mucus membranes (respectively; in the anus, vagina, cheek, under the tongue, or up the nose) and passes directly into the systemic blood stream, traveling straight to the brain and other organs without "first pass" liver metabolism taking place.
Smoking or vaporizing a drug allows the substance to be absorbed directly into the systemic bloodstream across the lining of the lungs, and so is even more immediate in effect and more efficient than any of the above routes. 
Finally, injecting a drug is even more immediate and efficient than smoking/vaporizing and inhaling. Subcutaneous injection is slightly less immediate than intramuscular injection, which is slightly less immediate than intravenous administration.
Some medications are 'pro-drugs'. They have little or no effect, but some of their metabolites are active drugs. The classic example is codeine, which has no real analgesic effect but is metabolised by the liver into morphine. A similar example is tramadol, which has little analgesic effect but is metabolised in the liver to O-desmethyltramadol and other active metabolites. Lysdexamfetamine has no effect, but is broken down by enzymes in red blood cells to form L-lysine, (a naturally occurring essential amino acid), and dexamphetamine. Avoiding first-pass liver metabolism conveys no advantage of immediacy or efficiency with pro-drugs.
With most psychoactive substances, first pass liver metabolism can make a very significant difference in the amount of the drug that ends up reaching the brain and other organs. When a patient is maintained on IV morphine in a hospital, and is then discharged into the community, they are typically transferred onto oral morphine pills. If the Doctor wants to provide enough oral morphine to ensure the same level of pain relief as the patient is receiving IV, they will typically increase the dose in mg threefold.
4 Recommendations
5th May, 2015
Robin Whelpton
Queen Mary, University of London
First-pass metabolism refers to the 'first passage' of drug through the liver, after absorption from the GI tract, as explained above. If the major proportion of an active drug is converted to inactive metabolites then the effect of first-pass will markedly reduce the effect of the drug (as explained above) and the oral dose may have to be increased or an alternative route of admistration chosen.
However, if the drug is is a pro-drug, that is inactive until it has been metabolised to active metabolites, first-pass metabolism may actually increase the activity and reduce the time to onset of effects compared to other routes of administration.
Furthermore, drugs may be metabolised by the gastric mucosa before they have even reached the liver. Any form of metabolism which results in less drug reaching the circulation may be referred to as 'pre-systemic' metabolism.  Pre-systemic metaboilsm includes first-pass metabolism.
4 Recommendations
9th Nov, 2020
Sumayya K. Mohammedamin
Hawler Medical University
previous explanations were all perfect.
But I'm wondering how is First pass related to phase 1 and 2? Is phase 1 happening while the drug is in the first pass process?
@
9th Nov, 2020
Robin Whelpton
Queen Mary, University of London
Phase 1 and phase 2 refer to the KINDS of metabolism. Phase 1 reactions usually add or reveal reactive groups. For example hydroxylation of diazepam to temazepam. Phase 1 reactions are often oxidations or hydrolysis reactions, although reductions also occur. In terms of first-pass metabolism in the liver - hydrolysis of pharmacologically inactive esters (prodrugs) to active drugs are important phase 1 reactions. Phase 2 reactions are conjugation reactions where an other molecule is added, for example glucuronic acid to form a glucuronide. Morphine has -OH groups that can be glucuronidated directly and this would be an example of first-pass metabolism when it occurs in the liver before morphine reaches the systemic circulation. Temazepam can form a glucuronide directly. Phase 2 metabolites are generally readily exceted but not always and can be toxic.
Let me push our book - Introduction to Drug Disposition and Pharmacokinetics, SH Curry & R Whelpton. Get your library to get you access.

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