Pharmacology: Pharmacokinetics (ADME)

Pharmacokinetics is the study of what the body does to a drug over time. It describes how a medication enters the body, where it goes, how it is chemically changed, and how it leaves. These processes determine practical clinical questions: How much should be given? How often? Should the dose be adjusted for kidney or liver disease? Will food or another medication change drug levels?

Pharmacokinetics is commonly organized into four linked steps known as ADME: absorption, distribution, metabolism, and excretion. Alongside ADME, concepts like bioavailability, half-life, clearance, and volume of distribution help translate drug behavior into dosing decisions.

Why ADME matters in real prescribing

A dose written on a prescription is not the same as the concentration a drug reaches in blood or at its target tissue. Two patients can take the same tablet and experience different effects because their bodies handle the drug differently. Pharmacokinetics explains variability and helps clinicians:

• Choose a route of administration (oral vs intravenous vs transdermal)
• Predict onset and duration of action
• Avoid toxicity, especially with narrow therapeutic index drugs
• Adjust dosing for organ impairment
• Anticipate drug interactions (for example, enzyme inhibition or induction)
• Design loading doses and maintenance doses for steady control

Absorption: how a drug gets into the body

Absorption is the movement of a drug from its site of administration into the systemic circulation.

Routes of administration and first-pass effect

• Intravenous (IV) administration bypasses absorption barriers entirely. Bioavailability is effectively 100%, and onset is rapid.
• Oral drugs must survive the stomach and intestine and then pass through the liver before reaching systemic circulation. This “first-pass” metabolism can significantly reduce the amount that reaches the bloodstream.
• Sublingual and buccal routes can reduce first-pass loss by allowing absorption directly into systemic circulation.
• Transdermal delivery can provide slow, steady absorption and avoid peaks and troughs seen with oral dosing.

Factors that influence absorption

Absorption depends on both drug properties and patient factors:

• Solubility and formulation: A poorly soluble drug may absorb slowly unless formulated to improve dissolution.
• Gastrointestinal motility: Faster transit time can reduce absorption for some medications.
• Food effects: Food can either enhance absorption (by increasing bile secretion and solubilizing lipophilic drugs) or impair it (by binding the drug or delaying gastric emptying).
• pH and ionization: Many drugs are weak acids or weak bases. Ionization affects membrane permeability and therefore absorption. While pH matters, real-world absorption is also shaped by surface area and transporters.
• Transport proteins: Some drugs rely on uptake transporters, while others are limited by efflux pumps such as P-glycoprotein.

Bioavailability: how much drug actually reaches the circulation

Bioavailability (F) is the fraction of an administered dose that reaches systemic circulation unchanged. For IV dosing, $F=1$. For oral dosing, $F$ is often less than 1 because of incomplete absorption and first-pass metabolism.

Bioavailability is central to switching between formulations or routes. A 10 mg IV dose is not automatically equivalent to a 10 mg oral dose when oral bioavailability is low. Clinically, this affects conversions such as IV-to-oral step-down therapy and explains why some medications require higher oral doses to achieve the same systemic exposure.

Distribution: where the drug goes after entering blood

Distribution describes the reversible transfer of drug between blood and tissues. It influences the speed of onset and which organs are exposed to higher concentrations.

Protein binding and free drug

Many drugs bind to plasma proteins such as albumin. Only the unbound (free) fraction can cross membranes, interact with receptors, and be cleared. Changes in protein binding can alter free concentration, particularly for drugs that are highly bound. However, changes in binding do not always translate into clinical harm because the body may adjust by changing clearance and distribution.

Volume of distribution (Vd)

Volume of distribution (Vd) is a useful “as if” volume that relates the amount of drug in the body to the measured concentration in plasma:

$$V_d=\frac{\text{Amount of drug in body}}{\text{Plasma concentration}}$$

• A low Vd suggests the drug stays largely in the bloodstream (common for large or highly protein-bound molecules).
• A high Vd suggests extensive tissue distribution (common for lipophilic drugs).

Vd is practical for calculating loading doses when rapid therapeutic levels are needed:

$$\text{Loading dose}\approx \frac{C_{\text{target}}\times V_d}{F}$$

Barriers and special compartments

Some tissues are protected by barriers that limit distribution:

• Blood-brain barrier: Lipophilic drugs or those with transport mechanisms enter more readily. Many antibiotics and anticancer agents have limited CNS penetration unless inflammation disrupts the barrier.
• Placenta and breast milk: Drug distribution can affect fetal and neonatal exposure, making pharmacokinetics essential in pregnancy and lactation.

Metabolism: how the body changes drugs

Metabolism (biotransformation) converts drugs into metabolites, often to make them more water-soluble for excretion. The liver is a major site, but metabolism can also occur in the gut wall, plasma, and other tissues.

Phase I and Phase II reactions

• Phase I reactions (often oxidation, reduction, hydrolysis) can alter drug activity and commonly involve the cytochrome P450 enzyme system.
• Phase II reactions (conjugation) typically attach a polar group, promoting elimination.

Metabolism can inactivate a drug, produce an active metabolite, or activate a prodrug. These distinctions matter clinically because effects may depend on metabolic capacity.

Drug interactions through enzyme inhibition or induction

Metabolic pathways are a common source of drug interactions:

• Enzyme inhibition can raise drug levels and toxicity risk by slowing metabolism.
• Enzyme induction can lower drug levels and reduce efficacy by speeding metabolism.

Interactions are especially important for medications with narrow therapeutic windows and for patients taking multiple chronic therapies.

Hepatic impairment

In liver disease, reduced enzyme activity and altered blood flow can decrease metabolic clearance. Dose adjustment may be needed, but the approach depends on whether the drug is primarily cleared by metabolism, how extensively it is first-pass metabolized, and whether active metabolites accumulate.

Excretion: how drugs leave the body

Excretion removes drug and metabolites from the body. The kidneys are the primary route for many medications.

Renal excretion

Renal elimination involves:

• Glomerular filtration (free drug is filtered)
• Tubular secretion (active transport can increase elimination)
• Tubular reabsorption (often influenced by urine pH and drug ionization)

Declining kidney function can cause drug accumulation, making renal dosing adjustments critical. In practice, clinicians often rely on estimated kidney function to adjust dose or dosing interval.

Biliary and other routes

Some drugs are excreted into bile and eliminated in feces. Enterohepatic recycling can return drug to the intestine for reabsorption, prolonging effect and sometimes creating secondary peaks in concentration.

Half-life, clearance, and steady state: timing and accumulation

Clearance (CL)

Clearance is the volume of plasma from which drug is removed per unit time. It summarizes the body’s ability to eliminate a drug and is central to maintenance dosing.

Half-life (t1/2)

Half-life is the time required for plasma concentration to fall by 50%. For many drugs with first-order kinetics:

$$t_{1/2}=\frac{0.693\times V_d}{CL}$$

Half-life guides dosing intervals and predicts how long a drug persists after stopping.

Steady state and accumulation

With repeated dosing, drug levels accumulate until the rate of drug administration equals the rate of elimination. This is steady state, typically reached after about 4 to 5 half-lives. The concept is essential when evaluating whether a regimen has had enough time to show full effect or whether a concentration-based lab value is interpretable.

Putting it all together: pharmacokinetics in everyday decisions

Pharmacokinetics is not abstract math; it is the logic behind safe, effective therapy:

• A drug with low bioavailability may require higher oral dosing or a different route.
• A drug with high Vd may need a loading dose to rapidly fill tissue compartments.
• A drug that is hepatically metabolized is vulnerable to enzyme-based drug interactions.
• A drug that is renally excreted often needs adjustment in kidney impairment to prevent toxicity.
• A drug with a long half-life may allow once-daily dosing but can take longer to reach steady state and longer to clear after discontinuation.

Understanding ADME provides a structured way to predict drug behavior, interpret patient responses, and tailor dosing to real-world clinical conditions.