Transl Clin Pharmacol.  2018 Mar;26(1):1-5. 0.12793/tcp.2018.26.1.1.

Understanding the pharmacokinetics of prodrug and metabolite

• Cho S
• Yoon YR

• KMID: 2420300
• DOI: http://doi.org/0.12793/tcp.2018.26.1.1

Abstract

This tutorial explains the pharmacokinetics of a prodrug and its active metabolite (or parent drug) using a two-step, consecutive, first-order irreversible reaction as a basic model for prodrug metabolism. In this model, the prodrug is metabolized and produces the parent drug, which is subsequently eliminated. The mathematical expressions for pharmacokinetic parameters were derived step by step. In addition, we visualized these expressions to help understand the relationship between pharmacokinetic parameters easily. For the elimination rate-limited and formation rate-limited metabolism, we analyzed the plasma drug concentration versus time curve of a prodrug administered intravenously.

Keyword

Pharmacokinetics; Prodrug; Formation rate-limited; Elimination rate-limited; Metabolism

MeSH Terms

Humans
Metabolism
Parents
Pharmacokinetics*
Plasma

Figure

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  Figure 1 A model to describe the kinetics of a prodrug and its metabolites. The prodrug (P) is metabolized or excreted unchanged according to the elimination rate constant (kel(P)). The drug (D) is eliminated according to the elimination rate constant (kel(D)). See text for details.

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  Figure 2 Amount-time profile for a two-step irreversible consecutive first-order reaction: A→k1B→k2C. The abscissa and ordinate represent time and amount of each species, respectively, in arbitrary units. The case illustrated was simulated using Microsoft Excel for k1 = 5, k2 = 1, and A0 = 1. The Bmax curve (dashed line) was obtained using Eqns. (11), (13), and (14) for k2 = 1. The dots represent Bmax for given values of k1. See text for details.

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  Figure 3 Semi-logarithmic concentration-time profile of a prodrug (P; blue line) and its formed metabolite (parent drug, D; red line). Simulations were performed using Microsoft Excel for three cases: (a) ERL metabolism where kf(D) > kel(D): kf(D) = 5, kel(D) = 1, and VD = VP = 1, (b) FRL metabolism where kf(D) < kel(D): kf(D) = 1, kel(D) = 5, and VD = VP = 1, and (c) FRL metabolism for VP/VD > kel(D)/kf(D) > 1: kf(D) = 1, kel(D) = 5, and VD = 0.05. VP = 1, and A0 = 10. Back extrapolation (dashed line; plotted using Eq. (19) or (21)) of the elimination phase slope (red line) provides an estimate of [D]0. The dotted line was plotted using Eq. (23) for the direct intravenous administration of a preformed (or synthesized) parent drug (D*) with the initial amount of D* (D*0) = 10 in (b) and 0.5 in (c). See text for details.

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