Читать книгу Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters - Страница 37

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)

(1.54)

Integrating Equation 1.54,

(1.55)

where AUC_M and AUC are the areas under the concentration‐time profiles of metabolite and parent drug, respectively. Recognizing that CL_f,M is the product of fraction metabolized (f_m ) and the total clearance (CL) of the parent drug,

(1.56)

Substituting for CL_f,M from Equation 1.56 in Equation 1.55,

(1.57)

f_m is obtained by measuring the amount of metabolite excreted in urine collected over a sufficient length of time (see Equation 1.29).