Chemotherapy Pharmacokinetics

Among factors which affect the pharmacokinetics of a drug are the route of administration (oral, parenteral, etc.), the site of administration, body weight, tissue absorption, and the dose administered. Practical pharmacokinetics are complicated by the fact that not everyone processes drugs in the same way.

When a chemotherapy agent enters the body, regardless of the route of administration, it undergoes absorption, separation into its constituent parts, metabolism and finally elimination.


Liberation is the release of the active constituent of the drug from its formulation. Before a drug can be absorbed by the body and deliver its therapeutic effects, it needs to be in a form that can be absorbed by the body. This is true for all drugs except intravenous solutions and some true solutions. The drug needs to be in the form of a solution before it can be absorbed, so dissolution, and hence liberation, is the first step in the pharmacokinetics of a drug. Liberation determines availability, rate of absorption and onset of action. After it has been liberated from its formulation the drug diffuses to the site of absorption. If the drug is administered intravenously, however, it is able to immediately circulate around the body via the bloodstream.


Absorption is the process by which the chemotherapy medicine enters the blood circulation. Absorption factors including formulation, physicochemical properties, route of administration and the way the specific patient’s body processes drugs. Routes of drug administration include oral, sublingual, parenteral, nasal, transdermal, urogenital, rectal and ocular.

Factors that influence drug absorption and bioavailability include permeation, which can include passive diffusion through the aqueous and lipid environment, and active transport, which comes into play in larger molecules.

In cases where the drug directly enters the bloodstream, absorption is likely to be more predictable and the drug’s bioavailability is close to 100%. Drugs that are taken orally dissolve in the stomach, but only commence absorption once they enter the intestines.

In order for the medicine to reach the malignant cells it must cross several semipermeable membranes. Drugs can cross the membranes by active transport, pinocytosis, passive diffusion or facilitated passive diffusion facilitated by cell receptors.


Aqueous diffusion takes place across the interstitial space, endothelial blood vessel lining, epithelial membrane tight junctions and through aqueous pores.

Mass transfer or diffusion is driven by Fick’s Law. Fick’s Law describes passive diffusion (flux) of molecules down a concentration gradient, as represented by the following equation:

J = -D x ΔC / Δ x

Where: J is the mass flux (moles / time x area)

D is diffusivity, i.e., the constant that describes how fast an object or solution diffuses

(D is expressed as area / time)

Δ = change in

C = Concentration, i.e., amount of mass in a given volume

(C is expressed as the amount of substance / volume)

Volume is expressed in 3 dimensions: length x length x length, e.g. mol / cm3, mol/L

x = the distance that the object is diffusing

(units of length such as m, cm)

To sum up, the flux is shown to be equal to the negative diffusivity multiplied by the change in concentration divided by the change in distance.

pH and the Henderson-Hasselbalch Equation:

Absorption of the drug depends on the dissolution rate, lipid/water solubility, blood circulation at the site of absorption, concentration at the absorption site and the area of absorbing surface.

The pH gradient across a membrane determines the absorption rate of the drug which is present in solution in both its ionized and unionized forms. Non-ionized drugs cross lipid membranes more easily as they are more lipid soluble.

The acid dissociation constant, pKa value, of a drug is the pH at which the drug is 50% ionized, and is a constant value for each drug. The  Henderson Hasselbalch equation demonstrates the ratio of charged molecules to uncharged molecules at a certain environmental pH, as follows:

pH = pKa + log [ [A-] / [HA] ]

where pKa is the pH at which the drug is 50% ionized,

[A-] is the concentration of a conjugate base,

and [HA] is the molar concentration of an undissociated weak acid

A simplified version of this equation would be:

pH = pKa + log (charged / uncharged)
Therefore, if the pH of the drug’s environment is known, the amount of
drug likely to be in its uncharged state can be calculated. (2, 5)


As absorption continues the drug is gradually distributed via the blood circulation to the tissues and organs. Drugs taken orally pass through the stomach and the liver before reaching the systemic circulation. Intravenous or intraarterial drugs bypass the stomach and liver.

The term Vd describes the volume of distribution, which is the ratio between the amount of drug in the body and the concentration of the drug measured in blood or plasma. This can be shown mathematically as:

Vd = (dose of drug) / (drug concentration)

Distribution tends to be uneven, however, due to variations in tissue perfusion, regional pH, tissue binding and the permeability of cell membranes.

As the body is a dynamic, constantly changing environment, the drug is simultaneously being absorbed, distributed and eliminated. In order to produce a model that will demonstrate distribution, the body is divided into theoretical compartments.

The central compartment includes the blood in the blood vessels and organs that are well perfused such as the heart, lungs, kidneys and brain. If the drug has a tendency to bind to plasma proteins, most of the drug will remain within the bloodstream and the Vd value will be low.

The central volume Vc (volume of the central compartment) can be expressed as:

Vc = Dose / Peak serum level

Peripheral compartments consist of tissue compartments that are less well perfused. These include adipose tissue, muscle, skeletal tissue and peripheral organs. Even if the tissue itself has a high affinity for a drug, distribution will be slow across poorly perfused tissues. The peripheral volume, Vt, is the totality of all the tissue spaces outside the central compartment. All drugs dissipate initially into the central volume and ultimately distribute into the peripheral volume. Therefore the sum of the central volume and the peripheral volume, Vt, make up the apparent volume of distribution, Vd .

Each drug has its own pattern of distribution within the body, with some drugs preferentially binding to adipose tissues or the extracellular fluid. Only unbound drug diffuses passively to the tissues where the drug exerts its pharmacological effects.

Some parts of the body are more accessible to drugs than others. For example, entry of drugs to the brain is restricted by the blood-brain barrier. The endothelial cells of brain capillaries possess tight junctions which slow the diffusion of water-soluble drugs and prevent unwanted substances such as bacteria and viruses from entering the brain.

Factors that affect the volume of distribution include the pKa of the drug, its lipid solubility, drug-plasma protein binding, and the individual  patient’s characteristics such as age, sex, weight and general state of health. (2, 6,7)

Another metric you see in pharmacokinetics is area under the curve (AUC), which is borrowed directly from calculus.  If you plot concentration of the drug in the blood over time, the area under that curve is sort-of, sometimes, and indicator of total drug exposure.

Metabolism of Chemo Drugs


Pharmacokinetics is complicated for chemo medications and the whole pharmacokinetics situation can get very messy if more than one medicine is used (combination chemotherapy) and if other drugs are administered (e.g. Mesna as a chemopreventive, carbamazepine as an anticonvulsant, ondansetron as an antiemetic.)  When calculating dosages, the full intake of medicines must be accounted for to avoid underdosing or overdosrng.

Older patients’ bodies process medicines differently than younger bodies – there is a gradual decline in kidney function with age in most people and the kidneys are key to removing chemotherapy drugs from the bloodstream.  Often there is occult renal impairment in the elderly and the chance of this occurring weighs on the oncologist’s minds, especially when a new drug or regimen is started.  Patients with liver dysfunction, due to either comorbidity or tumor, may not be able to metabolize or excrete drugs that are normally handled by the liver, thereby increasing the risk of the cancer drug affecting healthy parts of the body.

Once the Drug is in the Body

The therapeutic window refers to the dosage that doctors administer in an attempt to make the treatment both safe and effective.  Too low a dose is not effective in treating the disease.  Too high a dose and the side effects of the drug become detrimental or dangerous.  One challenge with chemotherapy is that the therapeutic windows tend to be narrow.  The toxic dose isn’t too much higher than the effective dose.  More on dosing.

One advantage of targeted therapies is that the therapeutic window may be wider.

Dosing Implications

Pharmacokinetics considerations are important in determining the proper dose of the chemo drug.  For years doses were based on the patient’s body surface area, but doctors have come to realize there is high inter-patient variability in plasma drug exposure and drug clearance. Other methods have been proposed either to reduce PK variability among patients or to decrease other sources of inter-patient variability such as errors in dose calculation or drug manufacturing. An ideal dosing calculation considers the metabolic pathway of each drug, estimates the activity of involved enzymes and calculates the dose accordingly, this is called phenotyping.. And it has been proved for many drugs such as Docetaxel and 5-flouriuracil. Further evidence is required to prove the reliability of other body size measures such as body mass index (BMI), lean body mass, ideal body weight (IBW) and adjusted ideal body weight (AIBW) in calculating anti-cancer drug doses.

A Note on Pharmacodynamics

The word “pharmacodynamics” is like pharmacokinetics, but it refers to a different phenomenon.  Pharmacodyamics describes the interaction of drugs with the body’s tissues.


Columbia University.  Drug absorption, distribution and elimination; pharmacokinetics.  (1)

Pharmacology 2000. General Principles: Pharmacokinetics  (2)

Merck Manuals.  Absorption (3)

University of Arizona.  Mass Transfer Equations: Fick’s Law (4)  Fun with pharmacokinetics.  (5)  Pharmacokinetic Concepts (6)