70
Biotransformations of Drugs and Chemicals
better than the rhesus monkey. The ex-
trapolation and scaling of drug metabolism
data from animals to humans, despite its
practical importance, is therefore still a
difFcult and imprecise science.
8
High-throughput Methods in Drug
Metabolism Studies
The acceleration of lead candidate dis-
covery by combinatorial synthesis and
high-throughput screening methods, com-
bined with the realization that metabolism
and pharmacokinetics are critical deter-
minants of a candidate’s success, has
led to efforts to develop methods that
allow
a
large
number
of
drug
can-
didates
to
be
screened
for
metabolic
properties
at
an
early
stage
of
the
drug
discovery
process.
The
proper-
ties of greatest interest are absorption,
metabolism, and the inhibition and in-
duction of individual cytochrome P450
enzymes. The approaches being pursued
include computational methods for the
prediction
of
probable
metabolic
pro-
Fles,
in vitro
studies of metabolic sta-
bility, reporter constructs in which the
activation of
receptors responsible for
the
induction
of
speciFc
cytochrome
P450
enzymes
is
readily
visualized,
DNA and protein microarray analysis of
changes in metabolic enzyme levels, and
high-throughput mass spectrometric ap-
proaches to determining actual metabolite
proFles.
See
also
Bioorganic
Chemistry;
Drug Bioavailability, Distribution
and Clearance Prediction.
Bibliography
Books and Reviews
Gibson, G.G.,
Skett, P.
(2001)
Introduction
to Drug Metabolism, 3rd edition, Nelson
Thornes, Cheltenham, UK.
Ioannides, C. (Ed.) (2002)
Enzyme Systems that
Metabolise Drugs and Other Xenobiotics
,John
Wiley & Sons, New York.
Mulder, G.J. (Ed.) (1990)
Conjugation Reactions
in Drug Metabolism. An Integrated Approach
,
Taylor & ±rancis, London, New York.
Ortiz de Montellano, P.R. (Ed.) (1995)
Cytochrome
P450: Structure, Mechanism, and Biochemistry
,
2nd edition, Plenum Press, New York.
Ortiz
de
Montellano, P.R.
(Ed.)
(2004)
Cytochrome P450: Structure, Mechanism, and
Biochemistry
,
3rd
edition,
Kluwer
Plenum
Press, New York, in press.
Phillips, I.R.,
Shephard, E.A.
(Eds.)
(1998)
Cytochrome P450 Protocols
, Humana Press,
Totowa, NJ.
Testa, B. (1995)
Biochemistry of Redox Reactions;
Metabolism of Drugs and Other Xenobiotics
,
Academic Press, New York.
Testa, B., Mayer, J.M. (2003)
Hydrolysis in Drug
and Prodrug Metabolism
, Wiley-VCH, Zurich.
Woolf, T.±. (Ed.) (1999)
Handbook
of
Drug
Metabolism
, Marcel Dekker, New York.
Primary Literature
Armstrong, R.N. (1999) Kinetic and chemical
mechanism of epoxide hydrolase,
Drug Metab.
Rev.
31
, 71–86.
Borhan, B., Jones, A.D., Pinot, ±., Grant, D.±.,
Kurth, M.J., Hammock, B.D. (1995) Mecha-
nism of soluble epoxide hydrolase. ±orma-
tion of an
α
-hydroxy ester-enzyme interme-
diate through Asp-333,
J. Biol. Chem.
270
,
26923–26930.
Benedetti, M.S., Tipton, K.±. (1998) Monoamine
oxidases and related amine oxidases as phase
I enzymes in the metabolism of xenobiotics,
J.
Neural Transm. Suppl.
52
, 149–171.
Bu, H.Z., Knuth, K., Magis, L., Teitelbaum, P.
(2001)
High-throughput
cytochrome
P450
(CYP) inhibition screening via cassette probe-
dosing strategy: III. Validation of a direct
injection/on-line guard cartridge extraction-
tandem
mass
spectrometry
method
for
previous page 744 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 746 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off