• For a drug to exert a systemic effect, it must first enter the bloodstream.

  • Bioavailability is the key pharmacokinetic parameter that quantifies this process, representing the bridge between the administered dose and the concentration of drug that the body's systems of distribution and elimination will act upon. This section introduces principles of bioavailability, consequences of first-pass elimination, and the relationship between bioavailability and the hepatic extraction ratio.

• Principles of Bioavailability (F)

  • Bioavailability, symbolized as F, is defined as the fraction or percentage of an administered dose of unchanged drug that successfully reaches the systemic circulation.

    • F accounts for both rate and extent of absorption.¹⁰

  • Absolute vs. Relative Bioavailability¹¹

    • Absolute bioavailability is the most fundamental measure.

      • Absolute bioavailability compares bioavailability of a drug administered via any non-intravenous route (e.g., oral, intramuscular, transdermal) to the bioavailability of the same drug given intravenously (IV).

      • Since an IV dose is administered directly into the systemic circulation, it is assumed to have 100% bioavailability, or F = 1 and provide the reference standard for comparisons.

    • Relative bioavailability is used to compare two different formulations of the same drug (e.g., a brand-name tablet versus a generic tablet, or a tablet versus a capsule).

      • This metric assesses whether the two formulations deliver the drug to the systemic circulation to the same extent and at the same rate Aand represents the basis of bioequivalence studies required for the approval of generic drugs.¹¹

  • Assessing Bioavailability

    • The most reliable method for determining bioavailability involves comparing the total systemic exposure to the drug after different routes of administration.

      • Exposure to the drug is quantified by the area under the plasma concentration-time curve (AUC) which is directly proportional to the total amount of unchanged drug that reaches the systemic circulation.

        • Absolute Bioavailability¹¹

          "Areas under the plasma concentration-time curves after intravenous and oral administration with complete absorption." Attribution: Alfie↑↓©, CC0, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:AUC_IVPO.svg

       

      • The absolute bioavailability (F) of an oral formulation, for example, is calculated using the following dose-normalized equation:

        • If the same dose is used for both oral and IV administration, the equation simplifies to the ratio of the AUCs.

           

• Factors Affecting Bioavailability

  • Drug Properties: The intrinsic physicochemical properties of the drug are especially important.

    • These properties include:

      • Aqueous solubility (which affects dissolution)

      • Stability in the acidic environment of the stomach and enzymatic environment of the intestine,

      • Molecular size, and

      • pKa (which determines its ionization state and ability to cross lipid membranes)¹²

  • Dosage Form and Formulation: The design of the drug product can significantly impact bioavailability.

    • Factors include:

      • Use of different salt forms

      • Particle size of the drug (micronization can improve dissolution), and

      • Type and amount of inactive ingredients, or excipients, used in the formulation. (Excipients can influence the drug's dissolution rate and stability).¹²

  • Physiological and Patient-Specific Factors: The patient's individual physiology plays a major role.

    • Factors include:

      • pH of gastrointestinal fluids

      • Rate of gastric emptying and intestinal motility

      • Presence or absence of food (which can enhance, delay, or reduce absorption), and

      • Patient's age

      • Disease states such as malabsorption syndromes (e.g., Crohn's disease) or liver disease can also profoundly affect bioavailability.

        • Genetic variations in the expression of drug transporters in the gut wall (e.g., P-glycoprotein) can cause significant inter-individual differences in drug absorption.^12,13

• First-Pass Elimination

  • For orally administered drugs, one of the most significant barriers to reaching the systemic circulation is first-pass elimination, also known as first-pass metabolism or presystemic metabolism.

    • First pass effect describes metabolism of a drug that occurs before it has a chance to be distributed systemically.¹⁴

• Sites of First-Pass Metabolism

  • After an oral drug is swallowed and dissolves, it must be absorbed across the wall of the gastrointestinal tract to enter the bloodstream.

    • The blood vessels draining the stomach and intestines do not lead directly to the general circulation; instead, they collect into the hepatic portal vein, which transports the blood directly to the liver.

    • This anatomical arrangement means that an orally absorbed drug must pass through two major sites of potential metabolism before reaching the systemic circulation.

  • The Gut Wall: The epithelial cells lining the intestine are metabolically active and contain a significant concentration of drug-metabolizing enzymes, particularly the cytochrome P450 isoform CYP3A4. A portion of the drug can be metabolized as it is being absorbed across the intestinal wall.¹⁴

  • The Liver: After passing through the gut wall and entering the portal circulation, the drug is delivered to the liver, which is the body's primary metabolic organ.

    • The liver can extensively metabolize the drug before it passes into the hepatic vein and enters the systemic circulation.¹⁴

• Clinical Consequences of First-Pass Metabolism

  • The first-pass effect can dramatically reduce the oral bioavailability of a drug.¹³  

    • For drugs that are highly susceptible to first-pass metabolism, such as nitroglycerin, lidocaine, and propranolol, only a small fraction of the oral dose may reach the systemic circulation unchanged.

      • This first-pass effect sensitivity has several important clinical consequences.

        • Such drugs may require much larger oral doses compared to parenteral (e.g., IV or sublingual) doses to achieve the same therapeutic effect.

        • Some drugs are so extensively metabolized on the first pass that they are not effective when given orally and must be administered by an alternative route that bypasses the liver (e.g., sublingual nitroglycerin, IV lidocaine).

        • There can be large inter-individual variability in the extent of first-pass metabolism, leading to unpredictable plasma concentrations and responses after oral administration.

  • Hepatic Extraction Ratio (E) and its Impact on Bioavailability

    • The concept of the hepatic extraction ratio (E), introduced earlier in the context of hepatic clearance, is directly and intimately linked to bioavailability.

      • E represents the fraction of drug removed by the liver in a single pass.

      • Therefore, the fraction of drug that survives the first pass through the liver is simply (1 - E).

    • Applicable Equation

      • Assuming a drug is completely absorbed from the gastrointestinal tract (i.e., the fraction absorbed, f_a, is 1), its oral bioavailability (F) is determined entirely by the fraction that escapes hepatic extraction. This relationship is expressed as: F = 1 - E.

      • If absorption from the gut is incomplete, the equation becomes F = f_{a *} (1 - E).

        • This equation demonstrates that bioavailability is fundamentally limited by both the extent of absorption from the gut and the extent of first-pass elimination by the liver.

        • A high extraction ratio inevitably leads to low oral bioavailability.

    • Clinical Implications Based on Extraction Ratio¹⁵

      • High-Extraction Drugs (High E): These drugs, by definition, have a low oral bioavailability (F is low).

        • Their bioavailability is also highly sensitive to any changes in the liver's metabolic capacity or blood flow.

        • This circumstance results in significant inter-patient variability in plasma concentrations following oral administration, making such patients more challenging to dose predictably.

      • Low-Extraction Drugs (Low E): These drugs are not significantly metabolized on the first pass and therefore tend to have a high oral bioavailability (F is high).

        • Their bioavailability is less affected by changes in liver function or blood flow but is more dependent on the extent of absorption from the gut.

      • The relationship F = 1 - E  gives rise to an important, non-linear amplification effect that explains the dramatic nature of some drug-drug interactions for high-extraction drugs.

        • Consider a drug with a high extraction ratio of E = 0.9, resulting in an oral bioavailability of F = 10% (1 - 0.9).

        • If a patient takes a second drug that is a potent inhibitor of the relevant metabolic enzyme, it might reduce the liver's metabolic capacity and decrease the extraction ratio by a seemingly modest amount, for example, to E = 0.7.

          • The new bioavailability would be F = 30% (1 - 0.7).

            • In this scenario, a 22% reduction in the extraction ratio has resulted in a 200% (three-fold) increase in the amount of drug reaching the systemic circulation.

              • This amplification effect is why interactions involving enzyme inhibitors (such as certain antifungal drugs or even grapefruit juice) can lead to dramatic and dangerous increases in the plasma concentrations of co-administered high-extraction drugs.

              • The impact on bioavailability is often much greater than the impact on the clearance of the drug once it is already in the systemic circulation.

Updated June 2025

• Summary of Key Pharmacokinetic Parameters and Governing Equations

  Parameter	Symbol	Conceptual Definition	Primary Governing Equation	Notes
  Volume of Distribution1	Vd	The apparent volume into which the drug distributors to produce the observed plasma concentration.	Vd = Amount of drug in body / plasma concentration	Influenced by lipophilicity, protein binding, tissue binding, patient fluid status. Used to calculate loading dose.
  Loading Dose2	LD	The initial dose given to rapidly achieve the target concentration.	LD =  Css * Vd) / F	For IV administration, F=1. Css Is the target steady-state concentration
  Clearance3	CL	The volume plasma cleared of drug per unit time. The most important parameter for maintenance dosing.	CL = DoseIV/AUC  OR CL = k * Vd	CLT = CLr +CLh + CLother
  Hepatic Clearance4	CLh	The volume of plasma cleared of drug per unit time by the liver.	CLh = QH * E	For high-E drugs, C≈ QH. For low-E drugs, CLh ≈ fu * CLint
  Renal Clearance5	CLr	The volume of plasma cleared of drug per unit time by the kidneys.	CLr = Rate of Renal Excretion / C	Net result of filtration, secretion, and reabsorption. CLr  = fe * CLT
  Elimination Half-Life6	t1/2	The time required for drug concentration to decreased by 50%.	t1/2 = (0.693 * Vd )/  CL	A dependent variable. Determines time to steady-state in dosing interval.
  Elimination Rate Constant7	k or kel	The fraction of drug eliminated per unit time.	k = CL / Vd	The slope of the log-linear plasma concentration decline. k  = 0.693 / t1/2
  Bioavailability8	F	The fraction of an administered dose that reaches systemic circulation.	F=(AUCoral/AUCIV) * (DoseIV/Doseoral)	For oral drugs, limited by absorption (fa) and first-pass effect: F = fa * (1-E)
  Extraction Ratio9	E	The fraction of drug removed by an organ in a single pass.	E = (CA - CV) / CA OR E = CLh / QH	Inversely related to bioavailability. Classifies drugs as high- or low-extraction.
  Maintenance Dose Rate10	MD Rate	The rate of drug administration required to maintain eight target steady-state concentration.	MD Rate = Css  * CL	For oral dosing, Dose / τ = (Css  * CL) / F
  Steady-State Concentration11	Css	The plateau concentration where rate of administration equals rate of elimination.	Css,avg = (F * Dose)/ CL * τ	Reached in about 5 half-lives. Level is proportional to dose and inversely to clearance.
  Michaelis Menten Elimination12	Rate	Describes saturable, capacity-limited elimination	Rate= (Vmax * C) / Km + C	Describes transition from first-order to zero-order kinetics. Important for drugs with narrow therapeutic windows.