Drug absorption refers to the process by which a drug enters the bloodstream after administration. There are many factors that can influence the rate and extent of drug absorption from the site of administration. Understanding these factors is important for healthcare professionals to optimize drug therapy. This article will discuss the three main factors that affect drug absorption: route of administration, dissolution and solubility, and first-pass metabolism.
Route of Administration
The route of drug administration is the path by which a drug enters the body. There are several common routes of administration including oral, sublingual, buccal, rectal, vaginal, parenteral (intravenous, intramuscular, subcutaneous), inhalation, and transdermal. The route of administration affects how quickly the drug enters the circulation and how much of the administered dose reaches systemic circulation.
Oral administration is the most common route for drug delivery. With oral administration, the drug must be absorbed through the epithelial cells lining the gastrointestinal (GI) tract. Absorption mainly occurs in the small intestine which has a large surface area. Oral bioavailability depends on drug solubility, dissolution, first-pass metabolism, and permeability across the intestinal wall. Due to variables along the GI tract, oral absorption can be highly variable with only a fraction of the oral dose being absorbed.
Sublingual and buccal administration involves placement of the drug formulation under the tongue or against the oral mucosa. This allows direct absorption into the rich blood supply in these regions, bypassing the GI tract. This route improves bioavailability of drugs that undergo extensive first-pass metabolism. Sublingual/buccal absorption can provide more consistent absorption compared to oral delivery.
Rectal administration involves inserting the drug into the rectum where it can be absorbed into the rectal veins without passing through the liver. This can also improve bioavailability for certain drugs compared to oral administration. However, absorption can be incomplete and highly variable.
Vaginal drug delivery provides an alternative route for system absorption and direct access to the uterus and ovaries. However, absorption can vary depending on vaginal pH, menstrual cycle changes, and vaginal secretions.
Parenteral routes like intravenous, intramuscular, and subcutaneous provide the most consistent drug absorption. With intravenous administration, the drug is injected directly into the vein and circulation for complete bioavailability. Intramuscular and subcutaneous injections deposit the drug into muscle or fat tissue from which the drug slowly enters capillaries and systemic circulation.
Inhalation delivers the drug directly to the lungs allowing rapid absorption into the systemic circulation. However, factors like particle size, air flow rate, and lung disease affect how much of the dose reaches the lungs.
Transdermal patches applied to the skin provide sustained delivery as the drug diffuses across the skin into circulation. However, the skin is a highly effective barrier against absorption. Only small lipophilic drugs can effectively cross the skin.
In summary, route of administration has a major impact on absorption rate and bioavailability. Intravenous injection provides the fastest absorption and highest bioavailability. Oral absorption is slower and more variable but offers the easiest and most convenient delivery. Transdermal, sublingual, buccal, rectal, vaginal, inhaled, and intramuscular/subcutaneous routes fall somewhere in between with various advantages.
Dissolution and Solubility
For drugs to be absorbed, they must first dissolve into a solution. Dissolution is the process by which a solid form of the drug dissolves. Aqueous solubility reflects how much drug can dissolve in water. These factors are extremely important for oral absorption since the drug must dissolve in GI fluids before it can be absorbed by the intestines. Drugs with poor water solubility will have slow and incomplete dissolution resulting in limited oral bioavailability.
There are two major types of formulations for oral administration – immediate release and modified release. Immediate release formulations (solutions, suspensions, tablets, capsules) are designed to dissolve and release the drug rapidly for quick absorption. However, drugs with low aqueous solubility will dissolve slowly causing variable absorption.
Modified release formulations are designed to control the dissolution rate. This helps maintain therapeutic blood levels over an extended period. Approaches include:
– Coating tablets and capsules with a polymer to slow dissolution
– Complexing drugs with cyclodextrins to increase solubility
– Using lipid-based formulations like self-emulsifying systems to keep the drug dissolved
– Formulating as a salt to enhance solubility
– Nanoparticle technology such as nanocrystals to increase surface area and dissolution rate
Solubility-Permeability Classifications
Based on solubility and intestinal permeability, drugs can be divided into four classes according to the Biopharmaceutical Classification System (BCS):
| Class | Solubility | Permeability |
|---|---|---|
| Class 1 | High | High |
| Class 2 | Low | High |
| Class 3 | High | Low |
| Class 4 | Low | Low |
– Class 1 drugs have optimal absorption properties with high solubility and permeability. Absorption is generally complete and consistent.
– Class 2 drugs have low solubility but high permeability. Their absorption is dissolution-rate limited. Strategies to enhance solubility can improve absorption.
– Class 3 drugs demonstrate high solubility but low permeability. Their absorption is permeation-rate limited. Drug particle size reduction and formulation approaches may provide modest improvements.
– Class 4 drugs exhibit poor solubility and low permeability. Their absorption is severely limited by both dissolution and permeation. Advanced formulations and prodrug strategies are required to enhance absorption.
In summary, the dissolution rate and solubility of a drug are critical determinants of oral absorption. Drugs must dissolve into GI fluids before permeation across the intestines can occur. Formulation approaches can help optimize dissolution and solubility.
First-Pass Metabolism
First-pass metabolism refers to drug metabolism that occurs before the drug reaches systemic circulation. After oral administration, drugs absorbed from the intestines go directly to the liver via the hepatic portal vein before entering the rest of the body. The liver contains high concentrations of metabolizing enzymes that break down drugs into metabolites. As a result, a significant fraction of an oral dose can be lost to first-pass metabolism, reducing the amount of active drug reaching circulation. This process varies based on the drug’s solubility, permeability, and metabolic stability.
Some key points about first-pass metabolism:
– It mainly occurs in the liver but can also take place in the gut wall. The small intestine and liver both contain high levels of the cytochrome P450 (CYP) family of metabolizing enzymes.
– Highly metabolized drugs such as opioid analgesics and calcium channel blockers are most affected, with oral bioavailability as low as 10-20% of the dose.
– First-pass metabolism exhibits high variability based on factors like enzyme expression and activity, liver blood flow, drug interactions, and disease states. This contributes to variable oral absorption.
– Strategies to avoid first-pass metabolism include alternative routes of administration, controlled release formulations, CYP inhibition, and prodrugs.
The fraction of the drug lost to first-pass metabolism is described by the hepatic extraction ratio:
Hepatic Extraction Ratio = Drug metabolized / Drug presented to liver
For drugs with a high extraction ratio, metabolism is blood flow-limited rather than perfusion-limited. Therefore, factors that alter liver blood flow such as foods, disease states, and drug interactions can affect first-pass metabolism. Drugs with low extraction ratios are perfusion-rate limited, and their metabolism is dependent on enzymatic activity.
In summary, extensive first-pass metabolism can significantly limit oral bioavailability of certain drugs. Alternative delivery routes that bypass the liver can minimize first-pass effects and improve absorption. An understanding of physicochemical properties, Biopharmaceutical Classification System class, enzyme kinetics, and extraction ratios helps predict the impact of first-pass metabolism on oral absorption.
Conclusion
The three major factors that determine the extent of drug absorption are:
1. Route of administration – Transport route affects rate of absorption and bioavailability. Intravenous has 100% absorption while oral absorption is slower and more variable.
2. Dissolution and solubility – Drugs must dissolve into GI fluids before they can permeate intestinal walls for absorption. Drugs with poor water solubility demonstrate limited and inconsistent oral absorption.
3. First-pass metabolism – Extensive metabolism in the gut wall and liver can significantly reduce oral bioavailability of highly metabolized drugs.
Understanding these key factors allows health professionals to select optimal drug products and dosage forms to maximize absorption. An appreciation of how physiology and drug properties impact absorption is crucial for providing effective pharmacotherapy. Continued research into novel delivery systems and absorption enhancers will further improve the development of drugs with optimal absorption and therapeutic effects.
