03&04 - Biotransformation Flashcards
phase 1 reaction result in
-relatively minor chemical modification of the parent compound
phase 1 reactions may result in the formation of functional groups which serve
as site for conjugation rxns
phase 1 reaction metabolite formed is more —
polar (more water soluble; less lipid soluble)
what are phase II reactions
these reactions are conjugations (i.e.. synthetic rxn with additional of another molecule)
phase II reaction drug or metabolite is rendered more — and —
- more polar
- less lipid soluble
phase II rxs with rare exception (eg. morphine), metabolites formed are
pharmacologically inactive
typical phase 1 reactions uses what 3 types of runs
- oxiations
- hydrolysis
- reductions
example of oxidations of typical phase 1 rxns
- cytochrome P450-linked (mainly in liver)
- epoxide hydrolase
- alcohol, aldehyde dehydrogenase
- xanthine oxidase (purines)
- monoamine oxidase (amines; mitochondria)
example of hydrolysis
ester and amide
examples of reductions
azo and nitro
what is cytochrome P-450
- mediates oxidation rxns (mixed-function oxidase)
- ancient “superfamily” with extensive phlyogenetic distribution
- 18 gene families in humans, encoding > 50 enzymes
CYP is an abbreviation for
cytochrome P450
CYP3 designates
family (>40% sequence homology)
CYP A designates
sub-family (>55% sequence homology)
CYP4 designates
specific gene/enzyme
CYP rxns are characterized as
- a mixed-function-oxidase, dependent on NADPH and molecular O2
- sort electron transport chain located in SER of liver and other organs
various isoforms of cytochrome P450 catalyze what
the oxidation rxn with a low degree of substrate specificity
substrates of CYP rxns must be
lipid soluble
what factors influence drug metabolism
- genetic P450 pattern/variant
- exposure to inducers
- up-regulation
- inhibition of P450 isoforms
- hepatic disease
- age
- sex
- nutritional status/diet
- adrenal and thyroid function
genetic p450 pattern/variant alleles yields an average of
6 to 30 fold variation in the average rate of drug metabolism
-individual differences for certain isoforms subject to pharmacogenetic variation can be even more striking
how can exposure to inducers (drug/ environment) influence drug metabolism
-content of many CYPs can be increased by exposure to certain drugs and exogenous compounds (2x-3x)
up-regulation usually occurs by
enhanced gene transcription following prolonged exposure to inducer
consequences of influencing drug metabolism
- increased rate of metabolism
- enhanced first-pass effect
- reduced bioavailability
- decreased [plasma]
inhibition of P450 isoforms may be due to
competition for enzyme active site, inactivation, or interactions with the heme group
consequences of inhibiting P450 isoforms
- increase [plasma] of the parent drug
- reduction in metabolite
- exaggerated and prolonged pharmacological effects
- increased likelihood of drug toxicity
what CYP enzymes are responsible for metabolizing most clinically important drugs
CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4,5
what CYP enzymes are primarily involved in drug metabolism
CYP1,2,3
drug metabolism represents
a potential source of significant drug interactions
-there are large individual differences in the average rate of drug metabolism due to genetic and environmental influences
what are 3 biliary-fecal routes
- transport systems
- biliary secretion
- enterohepatic cycle
where are biliary fecal-route transport systems located
in the heptocyte
function of biliary fecal route transport systems
actively uptake and secrete drugs and metabolites into the bile
what are biliary secretions
amphipathic, lipid-soluble conjugated metabolites with a MW of >300 may be secreted (MPR2) by the liver into the bile
enterohepatic cycle
active drug of its metabolite can be excreted in the feces or reabsorbed
glucuronide conjugates can be secreted and recovered to
the free,a chive drug in the intestinal lumen by bacterial enzymes
what is the formula for hepatic clearance
Cl organ= Q [CA-CV] = Q x E
Q= flow CA= [arterial] CV = [venous]
(CA-CV/CA) can be referred to as
the extraction ration of the drug (E)
what is intrinsic clearance
the intrinsic ability of the liver to eliminate a drug in the absence limitations imposed by blood flow
intrinsic clearance is a measure of
the Michaelis-Menten kinetic parameters for the eliminating process (ie. Vmax/Km)
high intrinsic clearance is relative to
blood flow
high intrinsic clearance is approximated and determined by
hepatic blood flow
how will decrease in blood flow affect high intrinsic clearance
will decrease Cl
decrease in blood flow due to aging, disease
will changes in plasma protein binding or enzyme activity affect high intrinsic clearance
will have minimal effect
low intrinsic clearance is relative to what
blood flow
low intrinsic clearance will be proportion to what
the unbound fraction of the drug in blood and the intrinsic clearance (ie. enzyme activity/biliary ecretion)
will changes in blood flow affect low intrinsic clearance
not significant effect on clearance
what will impact low intrinsic clearance
enzyme induction or changes in protein binding
what is the first-pass effect
orally administered drugs must pass through the liver before gaining access to the systemic circulation
what drugs will demonstrate reduced or low bioavailability
- drugs with high hepatic extractions
- drugs which are metabolized rapidly compared with their rate of absorption
what are the renal excretion methods
- glomerular filtration
- tubular secretion (active transport)
- tubular reabsorption
glomerular filtration clears
unbound drug
tubular secretion (active transport) occurs where
proximal tubule; energy dependent
when does tubular secretion (active transport occur)
as rate approaches renal blood flow?
tubular secretion (active transport) are unaffected by what
protein binding
tubular reabsorption
- concentration gradient
- Kp
- pKa
- influence of urinary pH
Renal clearance formula (ml/min)
(UxV)/P
U= concentration of drug in urine
V=volume of urine excreted per minute
P= concentration of drug in plasma
clearance value of a drug filtered and completely reabsorbed
Cl=0
clearance of a drug filtered and not reabsorbed
Cl~120ml/min
clearance of a drug filtered and (max) secreted
Cl~650ml/min
