style="font-size:15px;"> 1 Metabolite disposition is formation rate‐limited (kel,M > kf,M ) – commonly observed2 Metabolite disposition is elimination rate‐limited (kf,M > kel,M )
3 Neither of the two steps above are rate limiting
The first 2 cases are illustrated in Figure 1.9.
In the first case, when metabolite disposition is limited by its formation, the half‐life of parent is greater than that of its metabolite and the following equation holds:
CLM is the clearance of the metabolite, CLf,M is the metabolic clearance of the parent drug related to the formation of metabolite, VM is the volume of distribution of the metabolite, and V is the volume of distribution of the parent drug. The PK profiles of the parent drug and its metabolite are characterized by parallel terminal slopes (see Figure 1.9). The metabolite is eliminated as soon as it is formed. Consequently, the right‐hand side of Equation 1.50 becomes zero leading to
Rearranging Equation 1.52,
(1.53)
If the parent and metabolite have similar volumes of distribution, according to Equation 1.51, the clearance of the metabolite is greater than that of the parent drug. Thus, the amount of parent drug in the body is always greater than the metabolite. If the volume of distribution of the metabolite is much smaller compared to that of parent drug, then according to Equation 1.51, it is possible that the ratio of the elimination rate constants of the parent and metabolite is ≫1, provided VM /V is smaller than CLM /CLf,M . It is therefore not necessary that CLM should be greater than CLf,M . In other words, the amount of parent drug in the body need not be always greater than the metabolite, if the metabolite is polar and has a relatively low volume of distribution compared to the more lipophilic parent drug (see Figure 1.9). An example of this is propranolol where the amount of parent compound is less than that of the metabolite.
In the second case, the metabolite disposition is limited by its elimination and the half‐life of the metabolite is greater than that of its parent drug. This may lead to accumulation of the metabolite in the body and requires careful safety monitoring.
Lastly, in the event of comparable half‐lives of drug and metabolite, the terminal slope of the metabolite appears to decline slower than would be expected from its elimination rate constant, sustained by the parent drug.
Figure 1.9. Limiting conditions on metabolite disposition. (a) Formation‐limited metabolite kinetics when the volume of distribution of parent is similar to the volume of distribution of its metabolite. (b) Formation‐limited metabolite kinetics when the volume of distribution of parent is greater than the volume of distribution of its metabolite. (c) Elimination‐limited metabolite kinetics.
1.2.10.5 Drug‐Metabolite Plasma Concentration Relationships After Single Drug Administration
Detailed characterization of metabolite PK is limited by the availability of pure standards and chemical stability of metabolites. However, when the metabolite is likely to be active or toxic, the plasma concentration‐time profile of the metabolite is measured. Analogous to Equation 1.50, one can obtain Equation 1.54, recognizing that the product of elimination rate constant and amount of drug is the same as the product of clearance and concentration (see Equation 1.2)
Integrating Equation 1.54,
where AUCM and AUC are the areas under the concentration‐time profiles of metabolite and parent drug, respectively. Recognizing that CLf,M is the product of fraction metabolized (fm ) and the total clearance (CL) of the parent drug,
Substituting for CLf,M from Equation 1.56 in Equation 1.55,
(1.57)
fm is obtained by measuring the amount of metabolite excreted in urine collected over a sufficient length of time (see Equation 1.29).
1.2.10.6 Steady‐State Metabolite Kinetics
At steady state, the rate of change in the amount of metabolite in the body is zero, making the left‐hand sides of Equations 1.50 and 1.54 equal zero. It follows that the amount and concentration of the metabolite in the body at steady state are:
(1.58)
1.2.10.7 First‐Pass Metabolite Production
Following oral drug administration, some drugs have high hepatic and/or gut extraction due to first pass metabolism. The amount of a metabolite of interest in systemic circulation at any given time is
