Five pharmacokinetic parameters that are important in therapeutic drug monitoring include:

  1. Bioavailability. The bioavailability of a drug depends in part on its formulation. A drug that is significantly metabolized as it first passes through the liver exhibits a marked “first-pass effect,” reducing the effective oral absorption of the drug. A reduction in this first-pass effect (eg, because of decreased hepatic blood flow in heart failure) could cause a clinically significant increase in effective oral drug absorption.
  2. Volume of distribution and distribution phases. The volume of distribution of a drug determines the plasma concentration reached after a loading dose. The distribution phase is the time taken for a drug to distribute from the plasma to the periphery. Drug levels drawn before completion of a long distribution phase may not reflect levels of pharmacologically active drug at sites of action. Examples: Digoxin, lithium.
  3. Clearance. Clearance is either renal or nonrenal (usually hepatic). Whereas changes in renal clearance can be predicted on the basis of serum creatinine or creatinine clearance, there is no routine liver function test for assessment of hepatic drug metabolism. For most therapeutic drugs measured, clearance is independent of plasma drug concentration, so that a change in dose is reflected in a similar change in plasma level. If, however, clearance is dose dependent, dosage adjustments produce disproportionately large changes in plasma levels and must be made cautiously. Example: Phenytoin.
  4. Half-life. The half-life of a drug depends on its volume of distribution and its clearance and determines the time taken to reach a steady state level. In three or four half-lives, the drug level will be 87.5–93.75% of the way to steady state. Patients with decreased drug clearance and therefore increased drug half-lives will take longer to reach a higher steady-state level. In general, because non–steady-state drug levels are potentially misleading and can be difficult to interpret, it is recommended that most clinical monitoring be done at steady state.
  5. Protein binding of drugs. All routine drug level analysis involves assessment of both protein-bound and free drug. However, pharmacologic activity depends on only the free drug level. Changes in protein binding (eg, in uremia or hypoalbuminemia) may significantly affect interpretation of reported levels for drugs that are highly protein-bound. Example: Phenytoin. In cases in which the ratio of free to total measured drug level is increased, the usual therapeutic range based on total drug level does not apply.

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