Which change would most likely increase the half-life of a drug with hepatic clearance being the primary elimination route?

• A. Increased hepatic metabolism
• B. Increased hepatic blood flow
• C. Increased renal clearance
• D. Decreased hepatic metabolism

Answer: (D)

Half-life hinges on how quickly the body can clear the drug. The basic relationship t1/2 = 0.693 × Vd / CL shows that when clearance falls, half-life rises. If hepatic clearance is the main elimination route, the rate at which the liver metabolizes the drug largely sets how fast it is cleared. So, a decrease in hepatic metabolism slows the liver’s processing, lowers hepatic clearance, reduces overall clearance, and increases the half-life. In contrast, increasing hepatic metabolism would boost clearance and shorten the half-life. Similarly, increasing hepatic blood flow could raise clearance for high-extraction drugs and shorten the half-life, and increasing renal clearance would add another route and typically shorten the half-life if that route becomes more prominent. The change that would most likely increase the half-life is decreased hepatic metabolism.