SL32112-Lecture 20 - Rate limiting processes & metabolite kinetics 2

In a series of kinetic processes (A→B→C), what defines the rate-limiting step?

The slowest step in the sequence. It dictates the overall rate of the complete process, imposing the upper limit on the rate of all subsequent steps. This concept applies to drug absorption, elimination, and metabolite formation/elimination.

What are the two potential rate-limiting steps that control the plasma concentration decay of a metabolite (M) following IV bolus of the parent drug (A)?

• The rate of the metabolite's formation (kf​ or parent drug elimination rate k).

• The rate of the metabolite's elimination (kME​).

Identify the relationship between k and kME​ in Case 1: Formation Rate-Limited Metabolite Kinetics.

Case 1 occurs when metabolite elimination is much faster than its formation: kME​≫k (Metabolite t1/2​≪ Drug t1/2​). The metabolite is eliminated almost as soon as it's formed.

In Case 1 kinetics (Formation Rate-Limited), what rate constant determines the terminal slope of the ln Cmet​ vs. time plot?

The terminal slope reflects the elimination rate constant of the parent drug (k), meaning β=k. The slow formation of the metabolite controls its entire decay phase.

Provide examples of metabolites typically following Case 1 kinetics and explain why.

Glucuronide, sulphate, or glycine conjugates. They are much more polar and water soluble than the parent drug, leading to very rapid elimination (kME​ is high).

Identify the relationship between k and kME​ in Case 2: Elimination Rate-Limited Metabolite Kinetics.

Case 2 occurs when metabolite elimination is slower than its formation: kME​≪k (Metabolite t1/2​≫ Drug t1/2​). The metabolite accumulates.

In Case 2 kinetics (Elimination Rate-Limited), what rate constant determines the terminal slope of the ln Cmet​ vs. time plot?

The terminal slope reflects the elimination rate constant of the metabolite itself (kME​), meaning β=kME​. The slow elimination of the metabolite controls the final decay phase.

Provide examples of metabolites typically following Case 2 kinetics and explain why.

Acetylated or less polar metabolites. They are often less water soluble or less polar than the parent drug, leading to slower elimination (kME​ is low). Ex: Nordazepam (from Diazepam/Clorazepate).

What pharmacokinetic scenario is structurally analogous to metabolite kinetics (where drug → metabolite → eliminated)?

The extravascular administration model (where drug at absorption site → drug in body → eliminated). The absorption phase (kabs​) is analogous to metabolite formation (kf​ or k).