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10 Cards in this Set
- Front
- Back
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How does lipophilicity of drugs affect drug distribution and metabolism in the liver?
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- most drugs are lipophilic and can cross cell membrane to be taken up into liver
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What problem does drug lipophilicity present for excretion of the drug?
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-not readibly excretable by kidney in its lipophilic form
-must be rendered more hydrophilic by liver (or gut, lung, plasma, kidney) |
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What is drug metabolism?
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The irreversible transformation of drug in the body, which typically involves making it more polar to enhance renal excretion
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How does the liver metabolize drug?
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1. Phase I reactions (=oxidation,hydroxylation, reduction)
2. Phase II reactions (=conjugation) |
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What enzymes are responsible for Phase I reactions?
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Cytochrome P450 enzymes
2most important sub-families: CYP 3A4/5 metabolize 36% of drugs while CYP 2D6 metabolizes 19% |
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How do CYP enzymes metabolize drug?
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in general: add or uncover polar groups (-OH, NH2, COOH)to increase water solubility of drug
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Which enzymes are responsible for Phase II reactions?
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multiple enzymes (glucuronosyl transferases, sulfatases, glutathione S-transferases, acetyl and amino N-transferases) in ER or cytosol of hepatocytes
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What occurs in Phase II reaction?
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-large polar molecules are attached via ester linkages to drug, making them water soluble and excretable
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Where are CYP enzymes distributed in the liver?
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- selectively in the hepatic acinus: higher content in Zone 3
(explains zonality of hepatic lesions produced by drugs and toxins) |
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Are the products of Phase II reactions generally toxic, or non-toxic?
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-Non-toxic (thus considered to be detox reactions)
-exceptions: some glutathione conjugates undergo cysteine S-conjuate Beta-lyase mediated activation to from highly reactive intermediates |
