Non-linear pharmacokinetics

Non-linear pharmacokinetics refers to situations where changes in the dose of a drug do not result in proportional changes in the concentration of the drug in the bloodstream or its effects on the body. In simpler terms, the relationship between dose and drug levels is not a straight line (non-linear). This contrasts with linear pharmacokinetics, where doubling the dose results in a doubling of the drug's concentration in the blood.

Reasons for Non-Linearity:

1. Saturation of Enzymes:

   • Metabolism: Enzymes responsible for drug metabolism (e.g., cytochrome P450 enzymes) can become saturated at higher drug concentrations. Once these enzymes are fully occupied, the drug cannot be broken down at the usual rate, leading to a disproportionate increase in drug levels.
   • Example: Phenytoin, an anti-seizure medication, exhibits non-linear pharmacokinetics due to saturation of its metabolizing enzymes.

2. Saturation of Transporters:

   • Absorption: Drug transporters in the gut or tissues responsible for moving drugs into the bloodstream can become saturated at high doses, limiting absorption.
   • Excretion: Similarly, transporters in the kidneys or liver that help eliminate the drug from the body can get overwhelmed at high drug concentrations, reducing clearance.
   • Example: Vitamin C absorption becomes saturated, leading to reduced efficiency at higher doses.

3. Plasma Protein Binding:

   • Drugs often bind to plasma proteins like albumin. At high doses, the binding sites can become saturated, leaving more free (active) drugs in circulation, which can increase the drug's effects disproportionately.
   • Example: Drugs like salicylates can show this behavior.

4. Auto-Induction of Metabolism:

   • Some drugs can induce the enzymes that metabolize them, resulting in an increased rate of drug metabolism after repeated dosing. This makes the drug clear faster at higher doses or with prolonged use.
   • Example: Carbamazepine induces its own metabolism, resulting in non-linear kinetics.

5. Delayed or Non-Instantaneous Drug Distribution:

   • When a drug is administered, the distribution phase (when the drug is moving from the bloodstream to tissues) can sometimes take longer or be inefficient, leading to non-linearity.
   • Example: Digoxin has a complex distribution pattern that can cause non-linear kinetics.

Key Impact of Non-Linear Pharmacokinetics:

• It can make predicting drug levels challenging, as increasing the dose may result in disproportionately high blood concentrations, leading to toxicity. Conversely, reducing the dose may reduce the concentration too much, lowering efficacy.