What is the impact of enzyme inhibition on the PK of a co-administered drug?

• A. Increases clearance and decreases AUC
• B. Reduces clearance, increases AUC and t1/2
• C. Increases volume of distribution
• D. Causes faster absorption

Answer: (B)

When a metabolic enzyme that clears a co-administered drug is inhibited, the drug’s clearance falls because its metabolism is slowed. With slower clearance, the amount of drug remaining in the body stays higher for longer, so systemic exposure increases. The relationship is echoed in AUC being proportional to Dose divided by Clearance (for a given bioavailability): if clearance decreases, AUC goes up. At the same time, the elimination half-life is proportional to Vd divided by CL; if clearance drops while the volume of distribution stays roughly the same, the half-life lengthens.

Volume of distribution isn’t directly changed by enzyme inhibition, since it’s more about how the drug distributes between plasma and tissues, which depends on factors like lipophilicity and binding, not on metabolic rate. Absorption isn’t inherently sped up by blocking metabolism either, unless the inhibitor also affects absorption processes, which isn’t the typical outcome of metabolic inhibition.

So the scenario best aligns with reduced clearance and, consequently, increased AUC and longer t1/2.