PHARMACOKINETICS: Metabolism/Biotransformation (p.1) Drugs are eliminated from the body in two major ways: metabolism/biotransformation by the liver and/or excretion (mostly by the kidneys) Rich blood supply to the liver 20% arterial blood directly from heart 80% venous blood from GI tract (hepatic-portal vein) “First pass effect” 1. Liver, liver enzymes microsomal enzymes, P450 enzymes (CYP1A2, CYP2D6, CYP2C9, CYP3A4, CYP2C19, etc.) metabolize lipids, steroid hormones, and most drugs (see handouts) 2. Four types of chemical changes a. oxidation b. conjugation c. reduction d. hydrolysis 3. Inactive metabolites original molecule changed so that it no longer can activate RSs most metabolites are inactivePHARMACOKINETICS: Metabolism/Biotransformation (p.2) 3. Inactive Metabolites (cont.) usually the molecule becomes less able to pass out of bloodstream or pass through BBB (molecule becomes ionized, less lipid soluble, more water soluble) increased chance that molecule will pass into kidney and be excreted in urine 4. Active metabolites some metabolites are active, can get to & can activate RSs may have same or different effects as the original molecule some original molecules are inactive and only its metabolite is active implications for the drug’s duration of effect e.g. codeine – about 10% biotransformed into morphine (more powerful effects vs. codeine) Valium (diazepam) --- active metabolite extends duration 5. Enzyme inhibitors/suppressor e.g. Tagamet (cimetidine) implications for repeated dosing, & dose levels drug interactions 6. Enzyme inducers e.g. Tegretol (carbamazepine) e.g. ETOH & barbituratesPHARMACOKINETICS: Metabolism/Biotransformation (p.3) 6. Enzyme inducers (cont.) e.g. other inducers: PCBs (polychlorinated biphenyls), many plastics, insecticides, lubricants, heat-exchange fluids used in refrigerators/air conditioners note: P450 inducers effect on hormones, BC pills note: crucial importance of a good clinical Hx What drugs do you take? Why? When? How long? How much? Do you drink alcohol? Smoke cigarettes? Drink caffeinated beverages? Use OTC products? note: wide individual differences in rates/extent of metabolism (based on variations related to age, sex, race, health, other drug use) rapid metabolizers vs. slow metabolizers…clinical implications note: try to give pt. drug often enough & at right dosage to keep within the therapeutic range/index (where drug is effective but not toxic) related to issues of pt. compliance in taking drug… 1. on-going monitoring of pt. is necessary with repeated dosing, a dynamic