By Thomas F. Woolf

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Ealfd(m) is unity]. Oncef,,, is estimated, CL, is simply the product of f m and the total clearance of the parent drug CL, = fin . CL. An alternative approach to determine rate of metabolite formation and cumulative extent of formation is by the application of deconvolution analysis (30,31). l with a known input of the metabolite), the subsequent rate and extent of metabolite formation can be obtained by deconvolution (31) after any known input dose of the parent drug. This approach was applied to determine both metabolite formation rates andf,, for M6G after IV bolus and infusion doses of morphine, as shown in Fig.

Pharmacokinetics of Drug Metabolites 73 data are available. Because volume is a parameter that, to great extent, is dependent on physiocochemical properties of a compound and binding to tissues, this parameter when corrected for differences in plasma protein binding tends to be more amenable to interspecies scaling than is clearance (23,24). With a prediction of V(m) in humans based on interspecies scaling, Eq. (15) may be used to estimate k(m) for cases of FRL metabolism iffm or CL(m) are known.

Pathways Scheme 6 CL,? :, C(m)=A(m)/V(m) ___* *A( )rl Im CL21 Reversible conversion between metabolite and drug with parallel climination pathways for the parent drug and metabolite.

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