Bioavailability refers to the portion of an unaltered drug that enters the systemic circulation when administered through any route (Table 3-3). The area under the blood concentration-time curve (AUC) correlates with the extent of bioavailability if the drug’s elimination follows first-order kinetics (Figure 3-4). For intravenous drug administration, bioavailability is considered to be 100%. However, for orally administered drugs, bioavailability might be less than 100% due to two primary factors: incomplete absorption in the gut and first-pass metabolism by the liver.
A. Extent of Absorption
When a drug is taken orally, it may not be fully absorbed. For example, only 70% of a digoxin dose reaches systemic circulation, mainly because of incomplete gut absorption. Some drugs are poorly absorbed due to being either too hydrophilic (like atenolol) or too lipophilic (like acyclovir). Hydrophilic drugs struggle to cross lipid cell membranes, while lipophilic drugs are not soluble enough to pass through the water layer near the cells. Additionally, a reverse transporter like P-glycoprotein can pump drugs back into the gut lumen from the gut wall cells, decreasing absorption. Substances like grapefruit juice can inhibit P-glycoprotein and gut wall metabolism, leading to significantly increased drug absorption.
B. First-Pass Elimination
After absorption from the gut, portal blood transports the drug to the liver before it enters systemic circulation. Drugs can be metabolized in the gut wall (by enzymes such as CYP3A4) or in the portal blood, but primarily, the liver metabolizes drugs before they reach systemic circulation. The liver can also excrete drugs into bile. This overall reduction in bioavailability is known as first-pass elimination.
C. Rate of Absorption
Figure 3-4 illustrates the difference between the rate and extent of absorption. The rate of absorption depends on the administration site and drug formulation. Both the absorption rate and input extent can influence the clinical effectiveness of a drug. In Figure 3-4, different dosage forms (A, B, and C) show significant variations in clinical effect intensity. Dosage form B would need double the dose to achieve blood concentrations similar to dosage form A. Rate differences are crucial for single-dose drugs like hypnotics, where dosage form A would reach target concentrations faster than C, with higher and more prolonged levels above the target concentration. In multiple dosing, forms A and C would yield the same average blood concentrations, though form A would have slightly higher maximum and lower minimum concentrations.
Drug absorption is zero-order when the rate is independent of the remaining drug amount in the gut, such as when determined by gastric emptying rate or controlled-release formulation. When the dose is dissolved in gastrointestinal fluids, absorption rate is usually proportional to gastrointestinal concentration, termed first-order.
Extraction Ratio & the First-Pass Effect
Systemic clearance does not affect bioavailability but significantly influences the extent of availability via the extraction ratio (equation [8a]). Therapeutic blood concentrations can be achieved orally by increasing doses, although this leads to significantly higher metabolite concentrations compared to intravenous administration. Lidocaine and verapamil, with less than 40% bioavailability, are used for cardiac arrhythmias; however, lidocaine is not given orally due to CNS toxicity from its metabolites. Drugs with high hepatic extraction ratios include isoniazid, morphine, propranolol, and certain tricyclic antidepressants .
High extraction ratio drugs show significant bioavailability variations among individuals due to differences in hepatic function and blood flow, explaining the variability in drug concentrations among those given similar doses. Bypassing hepatic elimination (e.g., in hepatic cirrhosis with portosystemic shunting) greatly increases drug availability.
Alternative Routes of Administration & the First-Pass Effect
Different administration routes are used for various reasons (Table 3-3): convenience (oral), maximizing concentration at the action site while minimizing it elsewhere (topical), prolonging drug absorption (transdermal), or avoiding the first-pass effect.
The hepatic first-pass effect can be largely avoided with sublingual tablets and transdermal preparations, and to a lesser extent with rectal suppositories. Sublingual absorption directly accesses systemic veins, bypassing portal veins. The transdermal route has the same advantage. Drugs absorbed from the lower rectum via suppositories enter veins draining into the inferior vena cava, thus bypassing the liver, although suppositories may move upward where liver-draining veins predominate. Thus, about 50% of a rectal dose bypasses the liver.
While drugs administered by inhalation bypass the hepatic first-pass effect, the lung can act as a first-pass site through excretion and possibly metabolism for drugs given by parenteral routes.
Conclusion
Bioavailability is a critical concept in pharmacokinetics, referring to the proportion of a drug that reaches systemic circulation in an unaltered form. Intravenous administration provides 100% bioavailability, while oral administration often results in reduced bioavailability due to incomplete absorption and first-pass metabolism in the liver.
Key Factors Influencing Bioavailability:
Extent of Absorption: Oral drugs may not be fully absorbed due to their chemical properties or interactions with transport proteins like P-glycoprotein. Hydrophilic drugs may struggle to cross lipid membranes, while lipophilic drugs may have difficulty crossing aqueous layers. Inhibitors of P-glycoprotein, such as grapefruit juice, can increase drug absorption.
First-Pass Elimination: After absorption from the gut, drugs are transported to the liver via portal blood where they may be metabolized before entering systemic circulation. This process significantly reduces bioavailability and is quantified by the extraction ratio.
Rate of Absorption: The rate at which a drug is absorbed depends on its formulation and site of administration. Variations in absorption rate can impact the clinical effectiveness of a drug, especially in single-dose applications. Zero-order absorption occurs when the rate is independent of the drug amount in the gut, whereas first-order absorption is proportional to the gastrointestinal concentration.
Extraction Ratio and First-Pass Effect:
The extraction ratio significantly impacts bioavailability. Drugs with high hepatic extraction ratios, like lidocaine and propranolol, show considerable variations in bioavailability due to differences in individual hepatic function and blood flow. Bypassing hepatic elimination, such as in patients with hepatic cirrhosis, can significantly increase drug availability.
Alternative Routes of  Administration :
To avoid the first-pass effect, alternative routes such as sublingual, transdermal, and rectal administration can be used. These routes can enhance bioavailability by bypassing the liver to varying extents. Inhalation routes also bypass hepatic first-pass metabolism, although the lungs can act as a site of first-pass loss.
Understanding these factors is essential for optimizing drug delivery and ensuring effective therapeutic outcomes.
