3 Metabolism and Excretion

Learn how drugs are metabolized and excreted, what clearance and half-life measure, and how patient and drug factors can change elimination.

How drugs are metabolized

, also called biotransformation, chemically alters a drug. It occurs mainly in the liver, although the intestines, kidneys, blood, and other tissues can also contribute.

often makes a drug more water-soluble so it can be eliminated. Depending on the drug, may inactivate it, produce an active metabolite, or activate a that was initially inactive.

Liver enzymes carry out many metabolic reactions. Other drugs can inhibit these enzymes, slowing and potentially increasing drug exposure, or induce them, speeding and potentially reducing exposure. The clinical effect depends on the drug: faster may also increase the active effects of a .

How drugs leave the body

removes a drug or its metabolites from the body. The kidneys are a major route for many medicines. In the kidneys, substances may be filtered from the blood, secreted into urine, or reabsorbed back into the blood.

Other routes include elimination into bile and feces, or through the lungs for volatile substances. Some drugs are excreted largely unchanged; others must first be metabolized.

What clearance measures

Clearance describes how efficiently the body removes a drug from plasma. It is a volume of plasma cleared of drug per unit time, not the total amount of drug removed. Total clearance combines clearance by the kidneys, liver, and other routes.

In a simplified model, clearance is calculated as:

\mathrm{CL}=\frac{\text{rate of drug elimination}}{\text{plasma drug concentration}}

For a given dose, lower clearance generally means greater or more prolonged drug exposure. Reduced kidney or liver function can therefore lead a clinician to reconsider a medicine’s dose or dosing interval.

Half-life and elimination patterns

The is the time it takes for a drug’s plasma concentration to fall by half during elimination. With , a constant fraction is removed over each interval. For example, after four half-lives, about $6.25\%$ of the starting amount remains:

100\% \rightarrow 50\% \rightarrow 25\% \rightarrow 12.5\% \rightarrow 6.25\%

In a simplified, one-compartment model with first-order elimination, half-life is calculated as:

t_{1/2}=\frac{0.693 \times Vd}{\mathrm{CL}}

Here, $Vd$ is the apparent volume of distribution. A larger $Vd$ can lengthen half-life, while greater clearance can shorten it. If clearance falls and $Vd$ stays about the same, half-life increases. This formula is a useful model, but real drugs may have more complex distribution or elimination.

Some drugs show over particular concentration ranges. In this pattern, a roughly constant amount, rather than a constant fraction, is removed per unit time because elimination pathways are saturated. The decline cannot be described by one fixed half-life across all concentrations.

Factors that change drug elimination

Several patient and drug factors can change , , and clearance:

Liver function and blood flow: Liver disease or reduced hepatic blood flow can decrease clearance for drugs that depend on the liver.
Kidney function: Reduced renal function can slow elimination of drugs or metabolites excreted in urine, especially drugs eliminated largely unchanged.
Age and physiology: Age-related changes and other differences in organ function can affect clearance. The effect varies by drug and patient.
Genetics and drug interactions: Genetic variation, enzyme inhibition, and enzyme induction can change the rate of .
Drug characteristics and dose: A drug’s properties influence its route of elimination. At high concentrations, some metabolic pathways can become saturated, changing elimination behavior.

These factors can change drug exposure and the risk of effects or adverse effects. Medication doses should not be adjusted without appropriate clinical guidance.

Check your understanding

How differs from : chemically changes a drug; removes the drug or its metabolites from the body.
Half-life calculation: If a drug has a half-life of $6$ hours, then $18$ hours is $3$ half-lives. Assuming first-order elimination, about $12.5\%$ of the starting amount remains.
Reduced kidney function: For a drug eliminated mainly by the kidneys, clearance may decrease and half-life may increase.
First-order elimination: A constant fraction, rather than a constant amount, is removed per unit time.