Oral drug administration is one of the most convenient and common routes for delivering medications to the body. It offers ease of administration and high patient compliance. However, it requires sufficient drug to be absorbed in order to elicit the desired pharmacological effect. This blog describes a few critical concepts relating to oral drug absorption, the fraction of the drug absorbed, and the rate-limiting steps that affect this fraction.
Key Concepts
Oral drug absorption refers to the process by which a drug moves from the gastrointestinal (GI) tract into the systemic circulation. For an orally administered drug to exert its pharmacological effects, it must overcome several barriers:
- Dissolution: The drug must first disintegrate from its dosage form (tablet, capsule, etc.) and dissolve into the gastrointestinal fluids.
- Solubility: Adequate solubility is necessary to maintain a sufficient concentration of dissolved drug in the GI fluid for absorption to occur.
- Permeation through membranes: After dissolution and solubilization, the drug must cross the epithelial cells of the GI lining, which involves traversing biological membranes. Once the drug crosses the epithelial cells, it reaches the blood vessels where it is taken into systemic circulation and distributed to the site of action.
Each of these steps can influence the rate and extent of oral drug absorption, and can depen d on the properties of the drug and the formulation. Understanding the rate-limiting step is crucial in drug formulation and development as it can impact both the therapeutic efficacy and safety profile of a drug.
Fraction of Drug Absorbed
The fraction of drug absorbed (FA%) refers to the proportion of the orally administered drug that successfully reaches systemic circulation. It is often expressed as a fraction of the dose, ranging from 0% (no absorption) to 100% (complete absorption).
The drug absorption process can be influenced by factors such as the physicochemical properties of the drug (solubility, lipophilicity, molecular weight, and ionization), the formulation, and physiological factors like pH and bile acid secretion.
Pion Predictor Software: Optimizing Oral AbsorptionPion’s Predictor Software applies the mechanisms of the Gastrointestinal Unified Theoretical (GUT) framework1 to convert in vitro flux data to predictions of in vivo oral absorption and percent fraction drug absorbed (Fa%). When you apply Predictor software to flux data collected by Pion’s Rainbow Dynamic Dissolution Monitoring system, the Predictor data can help you understand the interplay between dose (Do), dissolution (Dn,) and permeability (Pn) to help you understand where to target formulation improvements.
- Dose Number (Do): Defined as the mass of the administered dose divided by the product of intestinal volume and solubility of the drug (Do = Mo / CsVo). Dose numbers of 1 and below indicate that the administered dose is completely soluble. Dose numbers above 1 indicate that the dose is not fully soluble in the gastrointestinal tract. For example, a Do = 10 would require 10 intestinal fluid volumes to fully dissolve the dose.
- Dissolution Number (Dn): Defined as the residence time of the dose divided by the dissolution time (𝐷𝑛 = Tres / Tdiss). A dissolution number lower than 1 indicates that the dose cannot fully dissolve in the time taken for intestinal transit, due to poor dissolution and/or solubility. A dissolution number higher than 1 indicates that the dose will fully dissolve; the higher the Dn the faster the dissolution process.
- Permeability Number (Pn): Defined as the permeability rate constant multiplied by the intestinal residence time (P𝑛 = Kperm/ Tres). A permeability number higher than 3 generally means that the compound has good permeability and is almost completely absorbed during transit along the gastrointestinal tract.
Assigning Rate-Limiting Steps
Predictor assigns an estimation of the rate-limiting step to absorption of the API based on the Do, Dn and Pn numbers calculated from the Fa% and defines whether the compound is subject to a permeability, dissolution, or solubility-permeability limitation. Solubility-permeability limitations can be further sub-categorized into solubility-permeability unstirred water layer or solubility-permeability epithelial membrane limited. Additionally, Predictor is able to classify the drug according to the BCS (Biopharmaceutics Classification System) based on the Do and Pn numbers determined from the Fa% result. Formulation scientists can then decide on a strategy for improving oral absorption outcome by overcoming the significant rate-limiting steps for their drug.
Conclusion
Oral drug absorption is a multi-step process influenced by drug properties, formulation, and physiological factors. The fraction of drug absorbed is a critical determinant of a drug's effectiveness. Understanding the rate-limiting steps in this process helps pharmaceutical scientists optimize drug formulations for maximum efficacy and therapeutic benefit. By targeting the rate-limiting factors, it is possible to enhance drug absorption, improve bioavailability, and ultimately ensure better therapeutic outcomes.
Contact Pion today to learn how our Predictor Software can help you optimize your drug formulation and improve oral absorption results. References 1. Sugano, K. Biopharmaceutics Modeling and Simulations: Theory, Practice, Methods, and Applications; John Wiley &Sons, Inc.: Hoboken, NJ, USA, 2012.
