8/27/ BIOTRANSFORMATION DR. NASIR ALI AFSAR

8/27/ CLEARANCE OF DRUGS Definition Why needed? Either Unchanged Metabolites Polarity of compounds

8/27/ BIOTRANSFORMATION Definition Sites Liver GIT Kidneys Others Lungs Skin

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/ Nonsynthetic or Phase I Reactions: Site

8/27/ Oxi dation Re duction Hy drolysis hydroxylations aromatic, aliphatic, nitrogen dealkylations(N-, S-, P) deaminations N-, S-, P- oxidations S-replacements epoxidations others azo reduction nitro reduction disulfide reduction others esters amides oxidoreductases oxidases monoamine oxidases mixed function oxidases oxidoreductases reductases esterases amidases peptidases lipases Nonsynthetic or Phase I Reactions:

8/27/ Nonsynthetic or Phase I Reactions: Cyt P450

8/27/ Nonsynthetic or Phase I Reactions: Cyt P450

8/27/ Nonsynthetic or Phase I Reactions: Cyt P450

8/27/ Enzyme Induction Enhance synthesis: Phenobarbital, Steroids Reduce rate of degradation: Substrate Stabilization Clotrimazole, Ethanol

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.