9.2

Bioavailability: Influencing Factors

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A drug’s bioavailability can be influenced by several factors.

Physicochemical properties, such as poor solubility, can decrease absorption. This limitation can be addressed using controlled-release or enteric-coated forms.

Drug stability in acidic gastric environments also impacts bioavailability. Acid-labile drugs should be administered as buffered or enteric-coated products to prevent degradation.

First-pass metabolism significantly reduces systemic drug levels. For example, propranolol undergoes extensive metabolism, reducing its systemic exposure. Meanwhile, prodrugs like valacyclovir metabolize into acyclovir, improving bioavailability.

Food also affects drug absorption. It enhances the systemic levels of isotretinoin but reduces didanosine bioavailability.

Lastly, drug–drug interactions can influence drug exposure via metabolizing enzymes and transporters. For example, enzyme inhibitors increase systemic levels by slowing metabolism, while enzyme inducers accelerate it, reducing plasma drug concentrations.

Overview

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Bioavailability refers to the extent and rate at which a drug reaches systemic circulation in its active form. Extent refers to the amount of the drug that makes it into circulation, while rate is the speed at which it enters circulation. It is influenced by several factors critical for optimizing drug formulations, dosing regimens, and therapeutic outcomes.

Physicochemical properties of drugs and formulations
The solubility, stability, and dissolution rate of a drug significantly impact its absorption. Poorly soluble drugs can benefit from specialized formulations, such as controlled-release or enteric-coated designs, which improve bioavailability. For instance, Neoral^® microemulsion enhances cyclosporine bioavailability compared to conventional Sandimmune^® formulations.

Drug stability and pH effects
Acid-labile drugs degrade in the low pH environment of the stomach, reducing bioavailability. Buffered or enteric-coated formulations protect these drugs from gastric acidity. Didanosine, for example, uses these strategies to maintain therapeutic levels.

First-pass metabolism
Drugs extensively metabolized in the liver during their first pass through the portal circulation exhibit reduced systemic availability. Propranolol, an antihypertensive, is one such example. Prodrugs like valacyclovir bypass this limitation, converting to active forms after absorption, thereby enhancing bioavailability.

Food effects
Food can either enhance, reduce, or have no significant impact on drug bioavailability. For example, food increases isotretinoin absorption but reduces didanosine bioavailability. In some cases, high-fat meals increase drug exposure, leading to safety concerns, as seen with efavirenz.

Drug-drug interactions
Concomitant drug administration can influence bioavailability via enzyme inhibition or induction. Enzyme inhibitors like ritonavir increase systemic drug levels by slowing metabolism, while inducers like rifampin accelerate metabolism, lowering drug levels and efficacy.

Transport proteins
Proteins such as P-glycoprotein play a significant role in drug absorption and clearance. Drugs that inhibit or are substrates for transport proteins, such as digoxin, show variability in bioavailability depending on transporter activity.

Effects of age
Aging alters drug bioavailability due to reduced liver mass, decreased perfusion, changes in body composition, and declining renal function. These changes can increase the bioavailability of drugs metabolized by the liver or excreted by the kidneys, requiring dose adjustments in geriatric patients.

Effects of disease states
Renal and hepatic impairments significantly affect drug elimination and metabolism. Renally excreted drugs often show increased bioavailability in patients with kidney dysfunction, while hepatic impairment reduces metabolism, leading to systemic drug accumulation. Both conditions necessitate careful pharmacokinetic evaluations to optimize dosing.

Understanding factors influencing bioavailability, such as drug properties, first-pass metabolism, food and drug interactions, age, and disease states, is essential for effective and safe drug therapy. These considerations guide formulation development, administration strategies, and individualized patient care.

Transcript

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Bioavailability

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Transport Proteins

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