What is the effect of enzyme inhibition on drug clearance and exposure?

• A. Inhibition decreases Clint, decreasing Cl, increasing AUC, risk of toxicity.
• B. Inhibition increases Clint, increasing Cl, decreasing AUC.
• C. Inhibition has no effect on exposure.
• D. Inhibition increases hepatic clearance.

Answer: (A)

Enzyme inhibition reduces the liver’s metabolic capacity, so intrinsic clearance (Clint) falls. Total hepatic clearance is determined by Clint and hepatic blood flow (Q) through the well-stirred relationship CL = (Q × Clint) / (Q + Clint). When Clint decreases, the overall clearance tends to drop, especially if Clint isn’t already far above Q. With lower clearance, the drug remains in the body longer, so exposure rises for a given dose (AUC = Dose/CL). That increased exposure can raise the risk of toxicity, and the elimination half-life lengthens as well (t1/2 ≈ 0.693 × Vd / CL). While the magnitude of the effect can vary with the drug’s extraction ratio, the general rule is that enzyme inhibition lowers clearance and increases exposure.