Biotransformation substrate binding

However, quinidine is not biotransformed by CYP2D6, even though it binds to this enzyme with high affinity [unbound A) < 1 nM (34)]. Quinidine is actually biotransformed by CYP3A4 (35), and is a competitive inhibitor of this enzyme [A) as low as 5.4 pM (36)], although its effects are highly dependent on the CYP3A4 substrate employed. 

Numerous metabolic pathways involving mixed-fimction oxidases, esterases, transferases, and hydroxylases exhibit selectivity toward stereoisomeric substrates. Of all disposition differences that stereoisomers may display, the greatest stereoselectivity is expected in biotransformation, because of the specificity of metabolic enzymes and isoenzymes. The overall differences in hepatic clearance of stereoisomers reflect not only differences in intrinsic clearance (activity of drug metabolizing enzymes) for the isomers but also the steric effects of plasma protein binding and hepatic blood flow. 

Often, PBPK models for toxicokinetics application require special considerations (e.g., volatile toxicants may incur tissue-air partition coefficients and alveolar elimination rates). Partition coefficients are generally obtained by measurement in the laboratory, tissue volume/blood flow data are mostly available from the scientific literature (with allometric scaling from species to species), and biotransformation data are usually obtained from in vivo and in vitro kinetic studies. Biochemical constants for metabolic pathways are captured using the maximum rate of reaction, or Vmax5 and the binding affinity of the particular substrate for the metabolizing enzyme. 

Second, microbial chemical transformations are accomplished by means of enzymes, proteins that act as catalysts. Catalysts bind with reactants and hold them in such an orientation that they more readily react. The products of the reaction are then released, leaving the catalyst ready to facilitate another transformation. (It is possible for an enzyme to be destroyed if a chemical mimics the proper substrate sufficiently to bind, but fails to react and subsequently release from the enzyme.) Because each enzyme is produced in response to a section of the genetic code (DNA) in the organism and many enzymes are extremely specific, it is possible that some strains of a species of bacteria may accomplish a certain chemical transformation while other individuals cannot. By using modern techniques of molecular biology, scientists can insert specific biotransformation capabilities into bacteria by means of genetic transfer. This procedure is easiest if the genetic material is associated with plasmids, which are small circular molecules of DNA that can exist independently within a bacterial cell. 

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