MED ORG II Flashcards
Range of short-term toxicity studies
2 Weeks to 3 Months
Orphan drugs are used to treat fewer than ____ people in the US
200,000
IND is submitted to __ and reviewed for ___
FDA, 30 days
This gives permission to market drug product
New Drug Application (NDA)
Phase 4 aka
Postmarketing Surveillance
Metabolism aka
Biotransformation
Essential tool for pharmacists in their role of selecting and monitoring appropriate drug therapy for their parents
METABOLISM
polar functional groups are introduced
into the molecule or unmasked by:
Oxidation, Reduction and Hydrolysis
FUNCTIONALIZATION PHASE
form in vitro after cell homogenization
and fractionation of ER
MICROSOMES
are primarily
associated with protein synthesis
Rough microsomes
contain a
class of oxidative enzymes called
MFOs
Smooth microsomes
MFO Requirements
- NADPH ; 2. Molecular Oxygen
cytochrome P450 reductase
NADPH
One mole of FLAVOPROTEIN
contains one mole each of ____, ____
flavin
mononucleotide (FMN) and
flavin adenine dinucleotide
(FAD)
Name based on light abs at
450nm when complexed with
CO
Cytochrome P450
Hemoprotein containing an iron
atom which can alternate
between ferrous (Fe+2) and
ferric (Fe+3) states
Cytochrome P450
Serves as terminal oxidase
Cytochrome P450
refers to the mixed-function oxidation of aromatic
compounds to their corresponding phenolic
metabolites
Aromatic
Hydroxylation
aromatic
compounds
ARENES
phenolic
metabolites
ARENOLS
Reactive Oxygen Specie
ARENE OXIDE
AH proceed initially through an epoxide intermediate called an
______ which rearranges rapidly and spontaneously to
the arenol
ARENE OXIDE
NIH Shift leading to the formation of ____
ARENOLS
AH May also acted upon by_____ leading to the
formation of ______
EPOXIDE HYDRASES, TRANS-DIHYDRODIOLS
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
