Variability in Drug Responses

• Ethnicity increases the likelihood of genetic variance
• Ethnicity increases the likelihood of other differences, such as diet, and smking
• Diet has implications for enzymatic activity and gut microbiome
• More enzymes are produced to regulate the poisons inhaled from smoking
• Pharmacokinetics, pharmacodynamics, adherence and disease progression all contribute to variability in drug response
• CYP1A2 is an important drug metabolising enzyme that also detoxifies and activates carcinogens
• CYP2D6, CYP2C9, and CYP2C19 are major polymorphic CYPs
• Substrates of CYP1A2


  caffeine, olanzapine, naproxen
• inducers of CYP1A2


  grilled meats, cruciferous vegetables, cigarette smoke
• Inhibitors of CYP1A2


  oral contraceptives, fluvoxamine, apiaceous vegetables
• Inducers send signals to produce more of the enzyme
• Inhibitors bind to the metabolic site of the enzyme to stop metabolism
• Higher enzymatic activity will be indicated by a higher concentration of a compound's metabolite
• we can measure the ratio between the concentration of the compound and its metabolite to infer enzymatic activity
• Paraxanthine is caffeine's major metabolite
• CYP1A2 activity was found to be lower in South Asians
• Smoking induces CYP1A2 activity
• Oral contraceptive use inhibits CYP1A2 activity
• Genetics explain little variability in CYP1A2
• Physiologically-based pharmacokinetic modelling is a mathematical representation of the human body accounting for physiology, anatomy and pharmacology
• Physiology = organ blood flow, volume
• Anatomy = model structure
• Pharmacology = physiochemical nature of the molecule, interaction with body systems