If a drug has a large volume of distribution and clearance remains constant, what happens to its elimination half-life?

• A. Shorter half-life.
• B. No change in half-life.
• C. Longer half-life.
• D. Unpredictable half-life.

Answer: (D)

The elimination half-life is determined by how widely a drug distributes in the body relative to how quickly it is cleared. The relationship is t1/2 = 0.693 × Vd / Cl. If clearance stays the same but the volume of distribution is large, the ratio Vd/Cl increases, so the half-life becomes longer. In other words, when a drug occupies a much larger apparent space (more tissue binding or more reservoirs), it takes more time for the drug to be cleared to half of its current level because drug must come out of those tissues first. This is a predictable effect: increasing Vd at a fixed Cl lengthens the elimination half-life. For example, doubling Vd while keeping Cl constant would roughly double t1/2.