Study Set Content:
Human liver P450s (blank) are
responsible for about 75% of all clinically relevant phase I drug
metabolism and thus for about 60% of all physiologic drug
biotransformation and elimination.
3A4, 2C9,2D6, 2C19, 1A2, and 2B6
Three P450 genetic polymorphisms
Debrisoquinsparteine oxidation
Ultrarapid metabolism
Genetic drug polymorphism involves the stereoselective
aromatic (4)-hydroxylation of the anticonvulsant
mephenytoin, catalyzed by CYP2C19.
occurs in 3–10% of Caucasians and is inherited as an
autosomal recessive trait.
Debrisoquinsparteine oxidation
In affected individuals, the CYP2D6 -dependent oxidations
of (blank) and other drugs are impaired. These
defects in oxidative drug metabolism are probably co-
inherited.
debrisoquin
due to the presence of CYP2D6 allelic variants with up
to 13 gene copies in tandem.
Ultrarapid metabolism
This ultrarapid metabolizer ( UM ) genotype is most
common in (blank), populations
that display it in up to one third of individuals.
Ethiopians and Saudi Arabians
As a result, these subjects require two-fold to three-
fold higher daily doses of (blank)(an
antidepressant and a CYP2D6 substrate) to achieve
therapeutic plasma levels.
nortriptyline
The poor responsiveness to antidepressant therapy of the
(blank) also clinically correlates with a higher
incidence of suicides relative to that of deaths due to
natural causes in this patient population.
UM phenotype
is
metabolized much faster to morphine, often resulting in
undesirable adverse effects of morphine, such as
abdominal pain.
Prodrug codeine
intake of high doses of codeine by a mother of the
ultrarapid metabolizer type was held responsible for the
(blank) of her breast-fed infant.
morphine induced death
Genetic drug polymorphism involves the stereoselective
aromatic (4)-hydroxylation of the anticonvulsant
mephenytoin,
Genetic drug polymorphism involves the stereoselective
aromatic (4)-hydroxylation of the anticonvulsant
mephenytoin, catalyzed by
CYP2C19.
This polymorphism, which is also inherited as an
autosomal recessive trait, occurs in(blank)of Caucasians
and (blank) of Japanese populations.
3–5% , 18–23%
In normal “ extensive metabolizers ” (EMs) ( S )-
mephenytoin is extensively hydroxylated by CYP2C19 at
the (blank)of the phenyl ring before its glucuronidation
4 position
In normal “ extensive metabolizers ” (EMs) ( S )-
mephenytoin is extensively hydroxylated by CYP2C19 at
the 4 position of the phenyl ring before its glucuronidation
and rapid excretion in the urine whereas ( R )-
mephenytoin is slowly (blank) to (blank), an
active metabolite.
N -demethylated, nirvanol
is metabolized only half as rapidly in persons
with genetically determined deficiency in pseudocholinesterase
(now generally referred to as butyrylcholinesterase [BCHE]) as
in persons with normally functioning enzyme.
Succinylcholine
Different mutations, inherited as autosomal recessive traits,
account for the
enzyme deficiency.
Deficient individuals treated with succinylcholine as a surgical
muscle relaxant may become susceptible to prolonged
respiratory paralysis called
(succinylcholine apnea)
Similar pharmacogenetic differences are seen in the acetylation
of
isoniazid.
The defect in slow acetylators (of isoniazid and similar amines)
appears to be caused by the synthesis of less of the (blank) enzyme rather than of an
abnormal form of it.
N-
acetyltransferases NAT2
