MED ORG II Flashcards by Xei Lee

Range of short-term toxicity studies

2 Weeks to 3 Months

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Orphan drugs are used to treat fewer than ____ people in the US

200,000

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IND is submitted to __ and reviewed for ___

FDA, 30 days

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This gives permission to market drug product

New Drug Application (NDA)

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Phase 4 aka

Postmarketing Surveillance

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Metabolism aka

Biotransformation

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Essential tool for pharmacists in their role of selecting and monitoring appropriate drug therapy for their parents

METABOLISM

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polar functional groups are introduced
into the molecule or unmasked by:
Oxidation, Reduction and Hydrolysis

FUNCTIONALIZATION PHASE

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form in vitro after cell homogenization
and fractionation of ER

MICROSOMES

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are primarily
associated with protein synthesis

Rough microsomes

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contain a
class of oxidative enzymes called
MFOs

Smooth microsomes

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MFO Requirements

NADPH ; 2. Molecular Oxygen

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cytochrome P450 reductase

NADPH

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One mole of FLAVOPROTEIN
contains one mole each of ____, ____

flavin
mononucleotide (FMN) and
flavin adenine dinucleotide
(FAD)

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Name based on light abs at
450nm when complexed with
CO

Cytochrome P450

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Hemoprotein containing an iron
atom which can alternate
between ferrous (Fe+2) and
ferric (Fe+3) states

Cytochrome P450

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Serves as terminal oxidase

Cytochrome P450

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refers to the mixed-function oxidation of aromatic
compounds to their corresponding phenolic
metabolites

Aromatic
Hydroxylation

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aromatic
compounds

ARENES

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phenolic
metabolites

ARENOLS

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Reactive Oxygen Specie

ARENE OXIDE

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AH proceed initially through an epoxide intermediate called an
______ which rearranges rapidly and spontaneously to
the arenol

ARENE OXIDE

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NIH Shift leading to the formation of ____

ARENOLS

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AH May also acted upon by_____ leading to the
formation of ______

EPOXIDE HYDRASES, TRANS-DIHYDRODIOLS

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AH may be acted upon by _____ in GSH to yield _____

SULFHYDRYL GROUP IN GSH, GSH ADDUCT

It is important to prevent the formation of ___by arene oxides

ROS

Major route of metabolism for phenylcontaining drugs

Aromatic Hydroxylation

Hydroxylation occurs at the ___

PARA POSITION

Microsomal aromatic hydroxylation reactions appear to proceed most readily in _____

activated (electron-rich) rings

If there are two or more phenyl rings, hydroxylation proceeds in the _____

Electron Rich Ring

There are certain compounds which are resistant to aromatic hydroxylation despite of the aromatic rings DUE TO presence of ___ atoms attached to the rings

MULTI-ELECTRONEGATIVE CHLORINE

The metabolic oxidation of olefinic carbon—carbon double bonds leads to the corresponding ___

Epoxide or Oxirane

The epoxide is cleaved by epoxide hydrases to form

trans-diols

Olefin Epoxidation: There are inhibitors such as ____ and _____

Cyclohexene oxide and Trichloropropene

– more stable than the arene oxides formed from aromatic compounds

Epoxides

susceptible to enzymatic hydration by epoxide hydrase to form trans-l,2- dihydrodiols (also called 1,2-diols or 1,2-dihydroxy compounds

Epoxides

Toxicity of olefinic compounds may result from their metabolic conversion to __________

chemically reactive epoxide

toxin found in peanuts

Aflatoxin

abnormal heme derivative

Green Pigments

The epoxide is reasonably stable and can be measured _____ in the plasma of patients receiving the parent drug

quantitatively

• Carbon atoms attached to aromatic rings

Benzylic position

Carbon atoms attached to aromatic rings (benzylic position) are susceptible to oxidation, forming the ____

Alcohol (or carbinol) metabolite

______ metabolites are often oxidized further to aldehydes and carboxylic acids

1⁰ alcohol

_______are converted to ketone.

2⁰ alcohol

Primary Alcohol Metabolite

Alcohol

____ generally does not lead to the generation of reactive intermediates

Allylic hydroxylation

Metabolic oxidation at the terminal carbon is referred to as

ω oxidation

Oxidation of the penultimate carbon atom (i.e., next-to-the-last carbon) is called

ω— I oxidation

Hydroxylation of the alpha-carbon atom attached directly to the heteroatom (N, O, S).

Oxidation Involving Carbon-Hetero Systems

Hydroxylation AKA

oxidation of the heteroatom

Primary aliphatic amines are biotransformed by oxidative deamination (through the carbinolamine pathway) or by ___

N-Oxidation

Primary Aliphatic Amine | Enzyme:

MFO

Endogenous Primary Amines | Enzyme:

MAO

Dealkylation of secondary amines gives rise to the corresponding ____ metabolite

PRIMARY AMINE

Major Biotransformation Pathway of Primary Aliphatic Amines

N-Oxidation

N-oxidation appears to be a major biotransformation pathway because ________ cannot occur

a-carbon hydroxylation

Primary aromatic amines are oxidized to ____ then further oxidized to ____

Hydroxylamines, Nitroso

N- alkyl substituents are also dealkylated through

N-Dealkylation

______also happens to the alpha carbon of the amide or phosphamide.

Hydroxylation

It involves the oxidation of the alpha carbon

Oxidative Odealkylation

It also involves the alpha carbon hydroxylation

Oxidation Involving Carbon-Sulfur Systems S-dealkylation

– addition of hydrogen or gain of electrons

Reduction

play an important role in the metabolism of many compounds containing carbonyl, nitro, and azo group

Reduction

____ groups are susceptible to conjugation

Hydroxyl and Amino groups

Reduction of N-oxides to __

Tertiary amines

Ketones are resistant to oxidation are reduced to ______

Secondary Alcohol

Aldehydes are reduced to form ____

Primary Alcohol

not recommended in diabetic patients with renal failure, because of the possible accumulation of its active metabolite

Acetohexamide

Active Metabolite of Acetohexamide

Hydroxyhexamide

The (R)( + ) enantiomer of the oral anticoagulant warfarin undergoes extensive reduction of its side chain ____ to generate the (R,S)( +) alcohol

Keto Group

Proceed via a hydrazo intermediate that is cleaved reductively to yield the corresponding aromatic amines:

Azo Reductions

reaction of water with substrate resulting in breaking scissile carbonheteroatom bonds

Hydrolysis

Hydrolysis is frequently __________ although serum pH may cause reaction

enzyme-mediated

Major biotransformation pathway for drugs containing an Ester functionality.

Hydrolysis

mediated by nonspecific esterases found in the liver, kidney, and intestine and pseudocholinesterases present in plasma

Ester hydrolysis

mediated by liver microsomal amidases. Esterases and deacylases

Amide hydrolysis

MED ORG II Flashcards

(76 cards)