8/27/ Phases Phase I - Nonsynthetic make polar by unmasking a functional group like -OH, -NH2, -SH. oxidation-add O, remove H reduction-remove O, add H hydrolysis - add H 2 O Phase II - Synthetic make very polar Generally act in tandem
8/27/ Enzyme Inhibition Binding/Inactivation of heme iron: Imidazoles, Macrolides Inactivation of the enzyme protein: suicide inhibitors: Chloramphenicol combination of above: Secobarbital
8/27/ Synthetic or Phase II Reactions: Involves high energy intermediates Glucuronidation, Acetylation, Methylation, Glutathione/ Glycine/ Sulfate/ Water Conjugation. Transferases in microsomes or cytosol Role of nutrition in regulation of drug conjugation
8/27/ Results of Biotransformation Biotransformed Drug or Poison active inactive active inactive more potent TOXIC less potent In general - nonsynthetic reactions precede synthetic reactions can produce active metabolites synthetic reactions produce inactive metabolites Drug or Poison
8/27/ Clinical Relevance Individual Differences Age & Sex Genetic Factors Diet & Environmental factors Drug interactions Diseases
8/27/ REFERENCES Goodman & Gilmans Pharmacological Basis of Therapeutics. Ed. 10 Pharmacology: by Range, Dale & Ritter. Ed. 4 Katzungs Basic and Clinical Pharmacology. Ed. 8.