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7 Cards in this Set
- Front
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consequences of drug metabolism |
1. less lipid soluble, now kidney can excrete it
2. less stored in fat 3. more water soluble 4. more ionized at physiological pH 5. less bound to plasma proteins 6. less able to penetrate cell membranes 7. more readily excreted in urine by the kidneys |
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general characteristics of drug metabolites |
1. more water soluble
2. more easily excreted by kidneys 3. frequently inactivates a drug (inactivated by liver) 4. metabolism MAY activate a drug (bioactivation) 5. Prodrug concept à prodrug (precursor) is not active, metabolite is active may have no, <, =, or > pharmacological activity than parent drug can sometimes be toxic |
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Explain the functional importance of drug metabolism as it relates to the elimination and excretion of drugs |
1. Biotransformation makes drugs more lipid soluble, more water soluble, more ionized, less bound to plasma proteins, etc (see above). This allows the metabolites to be more easily eliminated and excreted through the kidneys.
2. Significance of metabolism: Termination of a drug's pharmacological effect(s) & enhancement of its excretion. This allows intermediates to become polar, non-toxic, metabolites which can then be excreted. |
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Discuss the role of metabolism in acetaminophen toxicity |
Metabolism allows acetaminophen to be turned into non-toxic metabolites. The major pathway (95%, phase 2) uses glucoronidation & sulfation to create inactive, non-toxic metabolites, which can then be excreted in the urine. The minor pathway (5%, phase creates reactive toxic intermediates, but these can be neutralized into non-toxic metabolites through glutathione conjugation. |
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Describe the implications of an intermediary drug metabolite being more reactive than the parent compound |
1. the reactive toxic intermediates are actually more reactive than the parent compound (acetaminophen) so the MUST be converted to non-toxic metabolites in order for them to be excreted
2. glutathione conjugation converts the toxic metabolites to the non-toxic form 3. happens when there is more drug present than the metabolic enzymes can handle 4. enzymes become saturated in the major pathway (phase 2) and so excess drug is metabolized by the minor pathway (CYP450 enzyme) 5. in this case the glutathione becomes depleted à drug cannot be converted to non-toxic metabolite so the toxic metabolic becomes reactive à hepatotoxicity cellular necrosis |
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Discuss Phase I of drug metabolism |
1. adds hydroxyl (OH) or some other group (SH, COOH, NH2)
2. more polar means more H2O soluble 3. if polar enough, may be excreted 4. many phase I products not eliminated rapidly 5. metabolites may be inactive 6. over ½ of all drugs are metabolized by a group of P450 enzymes 7. usually prepares a molecule for phase II 8. usually produces minor changes in chemical structure, LS, and biological activity |
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Discuss Phase II of drug metabolism |
1. conjugation an adds "something" to the drug; big water soluble drugs
2. glucuronic acid, sulfate, glutathione, acetyl groups 3. usually forms a highly polar, inactive metabolite that is renal excreted 4. Phase I metabolite may be needed as a substrate for phase II metabolism 5. Glucuronidation – hooks glucuronite groups; most important 6. Acetylation 7. Glutathione conjugation 8. Glycine conjugation 9. Methylation 10. produce large changes in structure, biological activity and LS (big decreases) |
