Chemistry Reference
In-Depth Information
H
N
H
N
O
O
O
O
O
O
S
N
R
N
H
H
O
O
"Sedative-hypnotic"
"Mutagenic"
Stereospecific biotransformations to metabolites
H
N
H
N
O
O
O
O
OH
O
O
N
R
R
S
N
H
H
OH
O
O
(S)-5-Hydroxythalidomide
(3'
R
,5'
R
)-
trans
-5'-Hydroxythalidomide
Epimerization
H
N
O
O
O
N
S
R
H
OH
O
(3'S,5'
R
)-
cis
-5'-Hydroxythalidomide
Figure 1:
Thalidomide and stereospecific biotransformation to its metabolites.
The metabolic elimination of thalidomide (Fig.
1
) is mainly by pH-dependent spontaneous hydrolysis in all body
fluids with an apparent mean clearance of 10 L/h for the (
R
)-(+)- and 21 L/h for the (
S
)-(-)-enantiomer in adult
subjects. Blood concentrations of the (
R
)-(+)-enantiomer are consequently higher than those of the (
S
)-(-)-
enantiomer at pseudoequilibrium. The metabolites in humans have been studied both from the incubation of
thalidomide with human liver homogenates and
in vivo
in healthy volunteers. The
in vitro
studies demonstrated the
hydrolysis products 5-hydroxythalidomide and 5'-hydroxythalidomide while
in vivo
only the 5'-hydroxy metabolite
was found, in low concentrations, in plasma samples from eight healthy male volunteers who had received
thalidomide orally. The hydrolysis of the thalidomide enantiomers by
in vitro
incubation was shown by Meyring
et
al.
, to be stereospecific [10a].
The chiral centre of the thalidomide enantiomers is unaffected by the stereoselective biotransformation process.
(3'
R
,5'
R
)-
trans
-5'-Hydroxythalidomide is the main metabolite of (
R
)-(+)-thalidomide, which epimerizes
spontaneously to give the more stable (3'
S
,5'
R
)-
cis
isomer. On the contrary, (
S
)-(-)-thalidomide is preferentially
metabolized by hydroxylation in the phthalimide moiety, resulting in the formation of (
S
)-5-hydroxythalidomide
[10] (Fig.
1
).
It seems that a multitude of its pharmacological activities could be due not only to the mother molecule but also to
its numerous chiral and achiral metabolites. Because of this
in vivo
interconversion of thalidomide, it is difficult to
determine exactly the pharmacological effect of each enantiomer.
Thalidomide has been a subject of numerous studies, although the former is tainted from its past history. In 1998 the
U.S. Food and Drug Administration approved thalidomide for use in treating leprosy symptoms and studies indicate
some promising results for use in treating symptoms associated with AIDS, Behchet disease, lupus, Sjogren
syndrome, rheumatoid arthritis, inflammatory bowel disease, macular degeneration, and some cancers [11].
PHARMACOLOGY
The body with its numerous homochiral compounds being amazingly chiral selective, will interact with each
racemic drug differently and metabolize each enantiomer by a separate pathway to generate different
pharmacological activities.
