What is Pharmacokinetics?

Pharmacokinetics is defined by the four ADME processes. A change in any ADME process can alter a drug’s effectiveness and safety.

A: Absorption

This is the drug’s entry into the body. For an IV drug, this is 100% and instantaneous. For oral drugs, it’s more complex.

• Route of Administration: Oral (pills), sublingual (under the tongue), transdermal (patch), and inhalation all have different absorption profiles.
• Bioavailability (F): A key concept in absorption. If a 100mg oral drug has a bioavailability of 50% (F=0.5), only 50mg actually reaches the bloodstream.
• First-Pass Effect: The reason bioavailability is often low. Oral drugs are absorbed from the gut and go to the liver (via the portal vein). The liver metabolizes a portion of the drug *before* it reaches the rest of the body. This is the “first-pass effect.”

As detailed by StatPearls (2024), drugs with a high first-pass effect (like propranolol or lidocaine) are either given in much higher oral doses or cannot be given orally at all.

D: Distribution

This is where the drug goes after entering the blood.

• Protein Binding: Drugs travel in the blood by binding to proteins, primarily albumin. Only the “free,” unbound drug is active. If a drug is 99% protein-bound, only 1% of it is working. This is a common source of drug interactions.
• Volume of Distribution (Vd): This is a *theoretical* value that describes how widely the drug spreads into tissues.
  • A low Vd drug (like warfarin) stays mostly in the blood.
  • A high Vd drug (like digoxin) spreads extensively into tissues (fat, muscle). This means it’s hard to remove from the body with dialysis because very little of it is actually in the blood at any time.

M: Metabolism (Biotransformation)

This is the body’s chemical alteration of a drug, mainly in the liver, to make it easier to excrete.

• Phase I Reactions: Usually oxidation, often carried out by the Cytochrome P450 (CYP450) enzyme system. This is the most important pathway for drug metabolism.
• Phase II Reactions: Conjugation (adding a molecule) to make the drug water-soluble so the kidneys can excrete it.
• Prodrugs: Some drugs are administered in an *inactive* form (a prodrug) and must be metabolized into their *active* form (e.g., codeine is metabolized by CYP2D6 into morphine).

Understanding the CYP450 system, as explored in 2020 reviews, is critical because it’s the site of most metabolic drug interactions (enzyme inducers and inhibitors).

E: Excretion (Elimination)

This is the permanent removal of the drug from the body.

• Renal Excretion: The most common route. The kidneys filter the drug (or its water-soluble metabolites) from the blood into the urine.
• Biliary Excretion: Some drugs are excreted by the liver into bile, which then enters the feces.

Patient kidney function (measured by creatinine clearance or eGFR) is therefore critical for dosing many drugs. A patient in renal failure cannot excrete a drug, so it will build up to toxic levels unless the dose is drastically reduced.

Pharmacokinetics is a quantitative science. These parameters are what you will calculate in your biostatistics and pharmacology assignments.

Half-Life (T½) and Steady State (Css)

This is a critical clinical concept for dosing.

• Half-Life (T½): The time it takes for the plasma drug concentration to fall by 50%. This determines the dosing *interval*. A drug with a 4-hour half-life (like paracetamol) needs to be taken frequently. A drug with a 40-hour half-life (like fluoxetine) can be taken once a day.
• Steady State (Css): When you give a drug repeatedly, you reach a point where the rate of drug going *in* equals the rate of drug being *eliminated*. This is “steady state,” and it is the target concentration for therapeutic effect. It takes approximately 4 to 5 half-lives to reach steady state.

This explains why some drugs, like antidepressants with long half-lives, may take weeks to reach a therapeutic steady state.

Cmax, Tmax, and Area Under the Curve (AUC)

These parameters are seen on plasma-concentration time graphs.

• Cmax: The “peak” or maximum concentration the drug reaches.
• Tmax: The “time” at which Cmax occurs. A fast-acting painkiller has a very short Tmax.
• Area Under the Curve (AUC): Represents the *total* drug exposure over time. This is the most accurate measure of bioavailability.

Clearance (CL) and Volume of Distribution (Vd)

These two parameters *determine* the half-life.

• Clearance (CL): The body’s efficiency at eliminating the drug (e.g., L/hr). This is affected by liver and kidney health.
• Volume of Distribution (Vd): How widely the drug distributes.

The half-life is directly proportional to the Vd (a drug hidden in fat is harder to clear) and inversely proportional to Clearance (efficient clearance = shorter half-life).