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Overview of Pharmacokinetics

by Jennifer Le, PharmD, MAS, BCPS-ID

Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, through, and out of the body—the time course of its absorption (see Drug Absorption), bioavailability (see Drug Bioavailability), distribution (see Drug Distribution to Tissues), metabolism (see Drug Metabolism), and excretion (see Drug Excretion). Pharmacodynamics (see Pharmacodynamics), described as what a drug does to the body, involves receptor binding, postreceptor effects, and chemical interactions. Drug pharmacokinetics determines the onset, duration, and intensity of a drug’s effect. Formulas relating these processes summarize the pharmacokinetic behavior of most drugs (see Formulas Defining Basic Pharmacokinetic Parameters).

Formulas Defining Basic Pharmacokinetic Parameters

Category

Parameter

Formula

Absorption

Absorption rate constant

Rate of drug absorption ÷ amount of drug remaining to be absorbed

Bioavailability

Amount of drug absorbed ÷ drug dose

Distribution

Apparent volume of distribution

Amount of drug in body ÷ plasma drug concentration

Unbound fraction

Plasma concentration of unbound drug ÷ total plasma drug concentration

Elimination (metabolism and excretion)

Rate of elimination

Renal excretion + extrarenal (usually metabolic) elimination

Clearance

Rate of drug elimination ÷ plasma drug concentration, or elimination rate constant × apparent volume of distribution

Renal clearance

Rate of renal excretion of drug ÷ plasma drug concentration

Metabolic clearance

Rate of drug metabolism ÷ plasma drug concentration

Fraction excreted unchanged

Rate of renal excretion of drug ÷ rate of drug elimination

Elimination rate constant

Rate of drug elimination ÷ amount of drug in body

Clearance ÷ volume of distribution

Biologic half-life

0.693 ÷ elimination rate constant (for first-order elimination only―see Rate)

Pharmacokinetics of a drug depends on patient-related factors as well as on the drug’s chemical properties. Some patient-related factors (eg, renal function, genetic makeup, sex, age) can be used to predict the pharmacokinetic parameters in populations. For example, the half-life of some drugs, especially those that require both metabolism and excretion, may be remarkably long in the elderly (see Figure: Comparison of pharmacokinetic outcomes for diazepam in a younger man (A) and an older man (B).). In fact, physiologic changes with aging affect many aspects of pharmacokinetics (see Pharmacokinetics in the Elderly and see Pharmacokinetics in Children). Other factors are related to individual physiology. The effects of some individual factors (eg, renal failure, obesity, hepatic failure, dehydration) can be reasonably predicted, but other factors are idiosyncratic and thus have unpredictable effects. Because of individual differences, drug administration must be based on each patient’s needs—traditionally, by empirically adjusting dosage until the therapeutic objective is met. This approach is frequently inadequate because it can delay optimal response or result in adverse effects. Knowledge of pharmacokinetic principles helps prescribers adjust dosage more accurately and rapidly. Application of pharmacokinetic principles to individualize pharmacotherapy is termed therapeutic drug monitoring.

Comparison of pharmacokinetic outcomes for diazepam in a younger man (A) and an older man (B).

Diazepam is metabolized in the liver to desmethyldiazepam through P-450 enzymes. Desmethyldiazepam is an active sedative, which is excreted by the kidneys. Elimination half-life is inversely proportional to the terminal slopes of the curves; flat slopes correspond to long half-lives. 0 = time of dosing. (Adapted from Greenblatt DJ, Allen MD, Harmatz JS, Shader RI: Diazepam disposition determinants. Clinical Pharmacology and Therapeutics 27:301–312, 1980.)

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