By Paul G. Pearson, Larry C. Wienkers
This well timed, elevated re-creation is the definitive guide for knowledgeable drug metabolism and pharmaceutical scientists and people new to the field.Written by way of across the world popular authors, it offers built-in, accomplished assurance of primary facets of drug metabolism and the sensible purposes that support advisor researchers via key demanding situations in sleek drug discovery and improvement.
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The higher ratios of NLA/propranolol at equilibrium are due to a much low ratio of CL(m)/CL; however, V(m)/V must be lower still (see Eq. 15) to provide k(m)/k > 1, characteristic of FRL metabolism. Abbreviations: NLA, naphthoxylacetic acid; FRL, formation rate limited. Source: From Ref. 20. Equation 5 can also be rearranged to indicate that the rate of elimination of metabolite, k(m) Á A(m), approximates its rate of formation from the parent drug, kf Á D Á [eÀkÁt] ¼ kf Á A, where A is the amount of parent drug in the body at any time after the dose, kðmÞ Á AðmÞ ¼ kf Á D Á eÀkÁt ðEq: 7Þ Thus, with FRL metabolism, an apparent equilibrium exists between the formation and elimination of metabolite such that the ratio of metabolite to parent drug is approximately constant soon after a dose of the parent drug.
Therefore, it is difficult for unambiguous conversion of observed metabolite concentrations to amount of metabolite in the body. It may be possible, given availability of metabolite(s), to administer metabolite to animals to determine relevant pharmacokinetic parameters; however, extrapolation of pharmacokinetic values from animals to humans is complex and problematic. In general, volume terms more often extrapolate between species when scaling than do clearance estimates. If the preformed metabolite can be administered to humans, relevant pharmacokinetic parameters can be determined as commonly employed for the parent drug (16–19).
6. Woehler F, Frerichs FT. Concerning the modifications which particular organic materials undergo in their transition to the urine. Ann Chem Pharm 1848; 63:335. 7. Schultzen O, Naunyn B. The behavior of benzene-derived hydrocarbons in the animal organism. duBois-Reymond’s Arch Anat Physiol 1867:349. 8. Stadeler G. Ueber die flu¨chtigen Sa¨uren des Harns. Ann Chem Liebigs 1851; 77:17–37. 9. Munk I. Zur Kenntniss der phenolbildenden Substanz im Harn. Arch Ges Physiol Pfluegers 1876; 12:142–151. 10.
