Biopharmaceutical factors affecting metabolism


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Biopharmaceutical factors affecting metabolism

  1. 1. Biopharmaceutical Factors affecting Metabolism -Sajan Maharjan M.Pharm (1st Sem.) 18/02/2014 1
  2. 2. drug gets into bloodstream gets to site of action is “changed” so that it can be excreted leaves the body Definition Drug metabolism is a biochemical modification of pharmaceutical substances usually through specialized enzymatic activity. 18/02/2014 2
  3. 3. Metabolite A Inactive Enz. A Enz. B Metabolite B Active Enz. C Metabolite C Toxic Drug Enz. D Metabolite D Undetectable 18/02/2014 3
  4. 4. Mechanism Drugs Highly lipophilic lipophilic Polar Hydrophilic Accumulation (Storage in body tissues Phase-1 Metabolism (Bioactivation or Inactivation) Polar Phase-II Metabolism (Inactivation) Hydrophilic 18/02/2014 Execretion (Renal or biliary) 4
  5. 5. Factors affecting Drug Metabolism Chemical Factors Biological Factors Enzyme induction Age Enzyme inhibition Physicochemical properties of drug Diet Sex differences Species differences Strain differences Altered Physiological factors 18/02/2014 5
  6. 6. Chemical Factors Enzyme induction It is the phenomenon of incresed drug metabolising ability of enzymes by several drugs and chemicals. Consequences Active Metabolites Inactive Metabolites Increased pharmacological activity or TOXICITY Decreased pharmacological activity 18/02/2014 Altered physiological status due to enhanced metabolism of compounds Eg: sex hormones 6
  7. 7. Examples of enzyme induction Oral Contraceptive Steroids CYP3A4 Inactive, Excreted Induction Rifampin Acetaminophen CYP2E1 p-Quinone Imine (Toxic) Induction Ethanol 18/02/2014 7
  8. 8. Enzyme inhibition It is a decrease in the drug metabolising activity of an enzyme. The process of inhibition may be: Direct inhibition Indirect inhibition Repression Decrease in the enzyme content Competitive inhibition Altered physiology Due to nutritional deficiency or hormonal imbalance Non-competitive inhibition 18/02/2014 8
  9. 9. Examples of enzyme inhibition Terfenadine CYP3A4 Active Antihistamine Inhibition Erythromycin Ketoconazole Consequences of Inhibition • Increase in the plasma concentration of parent drug • Reduction in metabolite concentration • Exaggerated and prolonged pharmacological effects • Increased likelihood of drug-induced toxicity Enzyme inhibition is more important clinically than enzyme induction esp. for drugs with narrow therapeutic index. Eg: anticoagulants,antiepileptics,hypoglycemias,etc. 18/02/2014 9
  10. 10. Biological factors Age Neonates and infants (upto 1 year) Microsomal enzyme system is not fully developed Many drugs metabolised slowly Half life of caffeine In neonates: 4 days In adults: 4 hours Children (1 to 12 years) Elderly Reduced liver size Rate of metabolism reaches maximum Require large mg/kg dose than adults Half life of theophylline in children is 2/3rd of that in adults 18/02/2014 Reduced hepatic blood flow Reduced enzyme activity Decreased metabolism of drugs 10
  11. 11. Diet Enzyme content and activity is altered by dietary components Protein diet Fat free diet grapefruit Vitamins and minerals Vitamin A, B2,B3,C & E Enzyme synthesis is promoted Increased drug metabolising activity Depresses cytochrome P-450 levels Decreased drug metabolising activity Inhibit metabolism of some drugs Eg: Terfenadine 18/02/2014 Ca, Fe, Mg & ZN Retard metabolic activity of enzymes 11
  12. 12. Sex difference  Responsiveness to certain drugs is different for men and women.  Such variations are generally observed following puberty. So, sex related differences in the rate of metabolism could probably be due to sex hormones. Examples Studies in animals Male rats have greater drug metabolising capacity Studies in humans Women metabolise benzodiazepines slowly than men 18/02/2014 Women on contraceptive pills metabolise some drugs slowly 12
  13. 13. Species differences Differences are mainly quantitative but there are some qualitative differences too Examples In Phase-I reactions In Phase-II reactions Metabolism of amphetamine and ephedrine By aromatic oxidation By oxidative deamination • Variations are mainly qualitative. Glucuronide conjugation is an important route of metabolism in mammals, birds, reptiles, and amphibians, but not in fish. In mammals, cats lack the ability to conjugate phenols with Glucuronic acid but it dominates in pigs 18/02/2014 13
  14. 14. Strain differences Pharmacogenetics (Study of intersubject variability in drug response) Ethnic variations (variation among different races) Acetylation of isoniazid Metabolism of phenylbutazone, antipyrine Whites and blacks In monozygotic twins Very little or No difference In dizygotic twins Large difference Equal percent of slow and rapid acetylators found 18/02/2014 Japanese and Eskimo Slow acetylators dominate 14
  15. 15. Altered Physiological factors Pregnancy High levels of steroid hormones Maternal drug metabolising ability is reduced Diseased states Liver disease (hepatitis, jaundice etc) Reduction in hepatic drug metabolising ability 18/02/2014 Renal disease Oxidation of Vit.D. Conjugation of salicylates are impaired CCF, MI Decrease in blood flow to liver 15
  16. 16. Physicochemical properties of drug Molecular size and shape pKa Acidity/ Basicity lipophilicity Steric and electronic characters Interaction with the active site of enzyme Affects metabolic process Such an interrelationship is not clearly understood 18/02/2014 16
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