Dd - Pk Drug Metabolism

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which pathway tends to predominate? fastest or slowest

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fastest

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drug interactions are due to

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drugs affecting the metabolism of other drugs

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primary site of drug metabolism

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liver, but other tissues metabolize drugs too: kidneys, skin, etc

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most modifications of drugs occur in

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smooth ER of tissue cells

"microsomal fraction" of metabolism

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what is the most frequent drug metabolizing reaction

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oxidation

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Metabolic modifications tend to turn ____-soluble compounds into more ____-soluble compounds to facilitate excretion.

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o Metabolic modifications tend to turn lipid-soluble compounds into more water-soluble compounds to facilitate excretion.

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"Prodrugs": drugs,

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inactive when administered, that are activated only after being metabolized (ie codeine is inactive until metabolized to morphine).

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Phase I metabolism

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o Phase I metabolism involves adding an oxygen atom to the drug, removing hydrogen atoms, or splitting the structure of the drug (ie hydrolysis), but doesn't involve any modifying agents larger than that.
o Reactions: Oxidation [microsomal and nonmicrosomal], reduction, hydrolysis.

cytochrome P450
MFO - mixed function oxidation

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phase I main enzyme

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Main enzyme is cytochrome P450, which is an oxidizing enzyme

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microsomal oxidation rxns found in

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hepatic smooth ER

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CYP cycle is dependent upon

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NADPH and Iron

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hydroxylation makes drugs more or less soluble

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more soluble

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MFO system

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uses 2 oxygens

1 goes to oxidize drug compound

other incorporated into water

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Non-microsomal phase I enzymes

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• Oxidizers:
 ADH or alcohol dehydrogenase: NADH-dependent. Replaces an alcohol group (OH) with a aldehyde group (COH). Reversible reaction.
 ALDH or aldehyde dehydrogenase: NADH-dependent. Replaces an aldehyde group (COH) with a carboxyl group (COOH). Irreversible reaction.
 MAO or monoamine oxidase: replaces a 1o amine group (NH2) with an aldehyde group (COH). Irreversible reaction.
• For fun: notice that dopamine, serotonin, and melatonin (monoamine neurotransmitters) are metabolized by MAOs. Thus the antidepressant class of MAO inhibitors, or MAOIs, which prolong the circulation life of those neurotransmitters.

Reducers:
 Nitro reductions (NO2 -> NH2)
 Azo reductions (N=N -> NH2 + NH2)
 Carbonyl reductions (C=O -> COH)
Hydrolyzers:
 Mainly hydrolysis of esters and amides (amide hydrolysis is much slower, thus compounds containing amides have longer half-lives). Notice that esterases often convert prodrugs to their active forms.

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phase I oxidizers

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ADH
ALDH
MAO

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 ADH or alcohol dehydrogenase:

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NADH-dependent. Replaces an alcohol group (OH) with a aldehyde group (COH). Reversible reaction.

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 ALDH or aldehyde dehydrogenase:

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NADH-dependent. Replaces an aldehyde group (COH) with a carboxyl group (COOH). Irreversible reaction.

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 MAO or monoamine oxidase:

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replaces a 1o amine group (NH2) with an aldehyde group (COH). Irreversible reaction.
• For fun: notice that dopamine, serotonin, and melatonin (monoamine neurotransmitters) are metabolized by MAOs. Thus the antidepressant class of MAO inhibitors, or MAOIs, which prolong the circulation life of those neurotransmitters.

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phase I non-microsomal reducers

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 Nitro reductions (NO2 -> NH2)
 Azo reductions (N=N -> NH2 + NH2)
 Carbonyl reductions (C=O -> COH)

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hydrolyzers

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 Mainly hydrolysis of esters and amides (amide hydrolysis is much slower, thus compounds containing amides have longer half-lives). Notice that esterases often convert prodrugs to their active forms.

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Describe general characteristics of Phase II metabolism:

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Phase II metabolism involves attaching larger endogenous biochemical units (not just oxygen) to the drug by way of cofactor enzymes. This process is referred to as conjugation.

transferases
enterohepatic recirculation

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transferases typically seen in phase I or phase II metabolism

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phase II

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enterohepatic recirculation

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the drug is conjugated in the liver but excreted in the bile, which gets passed back into the intestine. Once there, the intestinal enzymes can remove the conjugated compound from the drug, beginning the drug's action cycle over again (assuming the drug can get back into the plasma from the intestine)-- this can prolong the effective life of the drug.
Conjugation pathways, in particular, can easily become saturated (not a large enough store of the compound it's using to conjugate to keep up with the influx of drug).
Conjugation usually results in highly water-soluble compounds that are readily excreted- but note some exceptions (below).

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Glucoronidation:

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glucoruronide (large endogenous molecule) transferred onto drug.
 Notice that conjugation does not always inactivate the drug; glucuronidated morphine, for example, stays pharmacologically active.

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Sulfation:

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transfer of a sulfur group. This makes the drug highly charged and highly soluble; however, the compound from which the SO4 group is derived is found in very limited quantities-- thus sulfation is an easily saturable conjugation.

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Acetylation:

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transfer of an acetyl (COCH3) group to the target group.
 N-Acetylation: addition of acetyl group to an amine nitrogen.
 Notice that acetylation can made the compound less, rather than more, soluble (this is the case with many N-acetylations).
 A lot of genetic variability in quantity of N-acetylating enzymes (specifically N-acetyltransferase 2): divides into a bimodal distribution (rapid or slow metabolizers). This can impact metabolism of isoniazid and other amine-containing drugs.

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Methylation:

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transfer of a methyl group to any target.
 Note that this usually makes the compound less water-soluble.

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Glutathione conjugation:

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not discussed, but note that glutathione metabolism is used to detoxify acetominophen derivatives. When you drink a lot of alcohol, your glutathione levels are depressed, which is why drinking and Tylenol don't mix and result in hepatic and/or renal tubular necrosis.

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phase I or II
more inducible

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phase I > phase II

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phase I or II saturability

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phase II > phase I

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Inducers:

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Phenobarbitol [1A2, 2C8, 3A4];
Phenytoin [2C9, 3A4];
Carbamazepine [2C9, 3A4];
Rifampin [1A2, 2C9, 2C18, 3A4];
Ethanol [2E1];
St. John's Wort [3A4];
Tobacco smoke (not nicotine)[1A2]

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2) Inhibitors:

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Cimetidine [2D6, 3A4, 1A2];
Erythromycin/Clarithromycin [1A2, 3A4];
Ketoconazole [3A4};
Fluoxetine (and other SSRIs) [2D6, 3A4];
HIV Protease Inhibitors [3A4];
Omeprazole [2C19]