Lesson · 40 min · Free
Absorption & Bioavailability
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Absorption & Bioavailability
Welcome to the first module in our Pharmacokinetics & Drug Metabolism course, focusing on the critical initial steps of drug action: Absorption and Bioavailability. Understanding these concepts is fundamental for predicting drug efficacy, designing appropriate dosing regimens, and interpreting patient responses. At an upper-undergraduate level, we will delve into the mechanistic aspects and quantitative considerations that govern how a drug enters the systemic circulation and the fraction of the administered dose that reaches its site of action. Absorption refers to the process by which a drug moves from its site of administration into the systemic circulation. This process is influenced by a myriad of factors, including the physiochemical properties of the drug (e.g., lipophilicity, molecular weight, pKa), the formulation (e.g., tablet, capsule, solution), and physiological factors at the absorption site (e.g., pH, surface area, blood flow, presence of transporters or efflux pumps). For orally administered drugs, absorption primarily occurs in the gastrointestinal tract, with the small intestine being a major site due to its extensive surface area and rich blood supply. Passive diffusion, facilitated diffusion, active transport, and pinocytosis are the primary mechanisms by which drugs cross biological membranes. Bioavailability (F) is defined as the fraction of an administered dose of unchanged drug that reaches the systemic circulation. It is a crucial pharmacokinetic parameter because it dictates the actual amount of drug available to exert its pharmacological effect. For intravenous (IV) administration, bioavailability is 100% (F=1) by definition, as the drug is directly introduced into the systemic circulation. For other routes, such as oral, intramuscular, or subcutaneous, bioavailability is typically less than 100% due to incomplete absorption and/or first-pass metabolism.
Factors Influencing Oral Bioavailability
Oral bioavailability is particularly complex due to several sequential barriers. These include: Disintegration and Dissolution: The solid dosage form must first disintegrate into smaller particles, and the drug must then dissolve in gastrointestinal fluids. The rate-limiting step for many poorly soluble drugs is dissolution. Permeability: The dissolved drug must then permeate across the intestinal epithelium into the portal circulation. This is influenced by the drug's lipophilicity (governed by logP and pKa) and the presence of membrane transporters. First-Pass Metabolism: Before reaching the systemic circulation, drugs absorbed from the GI tract pass through the liver via the portal vein. The liver contains numerous enzymes (e.g., cytochrome P450 enzymes) that can metabolize the drug, significantly reducing the amount reaching systemic circulation. This phenomenon is known as first-pass hepatic metabolism. Metabolism can also occur in the gut wall. The extent of absorption (f) and the extent of first-pass metabolism (Fg for gut wall and Fh for hepatic) contribute to the overall bioavailability: F = f * Fg * Fh Where Fg and Fh are fractions of drug surviving gut and hepatic metabolism, respectively. For instance, if a drug is 80% absorbed (f=0.8), 90% survives gut wall metabolism (Fg=0.9), and 70% survives hepatic first-pass metabolism (Fh=0.7), the overall oral bioavailability would be: F = 0.8 * 0.9 * 0.7 = 0.504 (or 50.4%) Determining bioavailability often involves comparing the Area Under the Curve (AUC) of plasma concentration-time profiles after extravascular administration (e.g., oral) to that after intravenous administration. The formula for absolute bioavailability is: F = (AUC_oral * Dose_IV) / (AUC_IV * Dose_oral) Where AUC represents the area under the plasma concentration-time curve, and Dose is the administered dose.
Key Takeaways:
Absorption is the movement of a drug from its administration site into systemic circulation. Bioavailability (F) is the fraction of unchanged drug reaching systemic circulation. IV administration has 100% bioavailability by definition (F=1). Oral bioavailability is influenced by dissolution, permeability, and first-pass metabolism (gut wall and hepatic). First-pass metabolism significantly reduces the amount of drug reaching systemic circulation for many orally administered drugs. Bioavailability is quantitatively determined by comparing AUCs from different routes of administration. Practice Exercise: A new antimalarial drug, Mefloquine-X, is being developed. In a Phase I clinical trial, a 100 mg oral dose resulted in an AUC of 250 µg·h/mL. A separate cohort received a 50 mg intravenous (IV) dose, yielding an AUC of 150 µg·h/mL. Calculate the absolute oral bioavailability of Mefloquine-X. If subsequent in vitro studies reveal that Mefloquine-X is highly susceptible to CYP3A4 metabolism in the liver, how might this finding explain your calculated bioavailability value, and what potential strategies could be employed to improve its oral bioavailability?
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