Thursday, June 24, 2021

First Pass Effect Explained

by | November 17, 2020 0

First pass effect, also known as first-pass metabolism or pre-systemic metabolism is the term used for hepatic metabolism of drug when absorbed and delivered through portal blood. It can be defined as any biotransformation suffered by drug molecules before reaching systemic circulation.

While first pass effect might be present in any administration route (except, maybe, intra-arterial administration), it will be considerably more significant for the oral route, since there the drug will face organs expressing high levels of biotransformation enzymes before reaching systemic circulation.

The greater the first pass effect, the lesser the amounts of the drug that reach the systemic circulation.

Orally administered drugs will be majorly absorbed in the small intestine and transported to the portal vein (which accounts for approximately 75% of the total liver blood flow) through the mesenteric vessels.

Blood passes from branches of the portal vein through liver sinusoids between “plates” of hepatocytes. Blood also flows from branches of the hepatic artery and mixes in the sinusoids to supply the hepatocytes with oxygen.

This mixture percolates through the sinusoids and collects in a central vein which drains into the hepatic vein.

The hepatic vein subsequently drains into the inferior vena cava, which carries deoxygenated blood from the lower and middle body into the right atrium of the heart. This blood will later go to the lungs before finally reaching systemic circulation

A significant fraction of the absorbed drug amount might be subjected to pre-systemic loss due to biotransformation in the intestinal walls, biotransformation and/or biliary excretion in the liver, or biotransformation in the lungs (note that these three organs are highly relevant in terms of drug metabolism).

This first-pass effect can be clinically relevant when the metabolized fraction is high or when it varies significantly from individual to individual or within the same individual over time, resulting in variable or erratic absorption.

Note that all the substances absorbed in the stomach and the intestines will have to pass through the liver before reaching systemic circulation, with the exception of lipids, which form chylomicrons that are not absorbed directly into capillary blood but transported first into the lymphatic vessel that penetrates each intestinal villus.

Chylomicron-rich lymph then drains into the lymphatic system and only then into blood, without participation of the portal system.

Substances absorbed through the sublingual mucosa also evade hepatic first-pass effect, since the veins originating there do not join the portal system. For its part, about two-thirds of the drug absorbed through the rectal route bypasses the hepatic first-pass metabolism as the rectum’s venous drainage is two thirds systemic (middle and inferior rectal vein) and only one-third hepatic portal system (superior rectal vein).

Important: Have in mind that, since enzymatic systems are saturable systems (and generally, but, not always, described through the Michaelis–Menten kinetics), the fraction of the dose whose absorption will be affected by the first-pass effect will largely depend on the drug flux to the metabolizing organ. If the metabolizing system is exposed to a large quantity of drug per unit of time, it could get saturated (this is particularly true for drugs administered in large doses).

The higher the amount of drug above the saturation condition, the higher the fraction of the dose that will survive (unchanged) the first pass effect.

The fraction of the dose absorbed (F) when the drug is given by any route of administration can be estimated by comparing the area under the plasma concentration-time curve (AUC) after administering the drug for that route with the area under the plasma concentration-time curve after administering the drug intravenously. Remember that the AUC is proportional to the amount of drug that has reached systemic circulation.

For example, if one wants to estimate the fraction of the dose absorbed for a drug given orally, we should compute

F = (AUCoral / AUCiv) x (Div / Doral)

An F below 1 suggests incomplete absorption of the drug, due to inappropriate release of the drug from the dosage form, drug degradation in gastric media, intestinal low permeability, and/or first-pass metabolism in the gut and/or liver.

Source

  • Talevi, A. and Quiroga, P. (2018). ADME Processes in Pharmaceutical Sciences: Dosage, Design, and Pharmacotherapy Success. Switzerland AG: Springer.



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