Enzyme induction, inhibition, and drug interactions

A drug interaction is a change in intrinsic clearance. The clearance CLint-elasticity is ~1 for low-extraction drugs (capacity-limited, interaction-sensitive: here 0.91) and ~0 for high-extraction drugs (flow-limited: 0.11). Inhibition raises bioavailability, induction lowers it (F 0.95→0.83). Grade [V]; typical DDI fold-changes [L].

Enzyme induction and inhibition multiply intrinsic clearance up or down. The well-stirred model predicts the regime signature: low-extraction clearance is CLint-elastic (~0.91, capacity-limited) and high-extraction clearance is CLint-inelastic (~0.11, flow-limited), with inhibition raising F and induction lowering it.

Interactions move intrinsic clearance

Co-administered inhibitors or inducers change the intrinsic clearance CLint of the affected drug. Whether that matters depends on the extraction regime — the same split (flow-limited vs capacity-limited) that governs the healthy liver.

The regime signature, and the direction

Measuring the CLint-elasticity of hepatic clearance, the low-extraction drug is capacity-limited with elasticity 0.91 (clearance ≈ fu·CLint, so it tracks CLint almost one-for-one), while the high-extraction drug is flow-limited with elasticity 0.11 (clearance ≈ hepatic blood flow, nearly CLint-independent). The direction is correct too: for the capacity-limited drug, inhibition (CLint down) raises bioavailability 0.91→0.95 and induction (CLint up) lowers it 0.91→0.83. So the engine predicts which drugs are vulnerable to interactions (low-extraction, capacity-limited) and which are buffered (high-extraction, flow-limited) — the mirror of the shunt result, under a perturbed CLint rather than a perturbed flow.