Current Drug Metabolism, Volume 2, Number 1, 2001
Multiple Oxidants in Cytochrome P450
Catalyzed Reactions:
Implications for Drug Metabolism Pp. 1-16
Alfin D. N. Vaz
Enzyme Kinetics of Cytochrome P450-Mediated
Reactions Pp. 17-36
Magang Shou, Yuh Lin, Ping Lu, Cuyue Tang,
Qin Mei, Dan Cui, Wei Tang,
Jason S. Ngui, C. Charles Lin, Rominder
Singh, Bradley K. Wong,
James A. Yergey, Jiunn H. Lin, Paul G.
Pearson, Thomas A. Baillie,
A. David Rodrigues and Thomas H. Rushmore
Pharmacology of Chiral Compounds:
2-Arylpropionic Acid Derivatives Pp. 37-51
M.F. Landoni and A. Soraci
Pharmacodynamics of High-Dose Chemotherapy Pp. 53-66
Yago Nieto
Bestatin as an Experimental Tool in Mammals Pp. 67-85
O. A. Scornik and V. Botbol
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Multiple Oxidants in Cytochrome P450
Catalyzed Reactions:
Implications for Drug Metabolism
Alfin D. N. Vaz
The activation of molecular oxygen by Cytochromes P450 to
the ultimate mono-oxygen oxidant species involves three distinct dioxygen
species coordinated to the heme iron. These intermediates have different
chemical properties, and have recently been proposed to participate in some
Cytochrome P450- catalyzed
oxidation reactions. This article reviews the extent of our current knowledge
on the roles proposed for the heme- peroxo, hydroperoxo, and superoxo complexes
in various reactions. The extent to which such species contribute to the
breadth of reactions catalyzed by Cytochrome P450 has yet to be defined, and
more definitive experiments are needed to establish such species in the
reactions they are proposed to effect.
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Enzyme Kinetics of Cytochrome P450-Mediated
Reactions
Magang Shou, Yuh Lin, Ping Lu, Cuyue Tang,
Qin Mei, Dan Cui, Wei Tang,
Jason S. Ngui, C. Charles Lin, Rominder
Singh, Bradley K. Wong,
James A. Yergey, Jiunn H. Lin, Paul G.
Pearson, Thomas A. Baillie,
A. David Rodrigues and Thomas H. Rushmore
The most common drug-drug interactions may be understood
in terms of alterations of metabolism, associated primarily with changes in the
activity of cytochrome P450 (CYP) enzymes. Kinetic parameters such as K m , V max , K i and K a , which describe metabolism-based
drug interactions, are usually determined by appropriate kinetic models and may
be used to predict the pharmacokinetic consequences of exposure to one or
multiple drugs. According to classic Michaelis-Menten (M-M) kinetics, one
binding site models can be employed to simply interpret inhibition (pure
competitive, non-competitive and uncompetitive) or activation of the enzyme.
However, some cytochromes P450, in particular CYP3A4, exhibit unusual kinetic
characteristics. In this instance, the changes in apparent kinetic constants in
the presence of inhibitor or activator or second substrate do not obey the
rules of M-M kinetics, and the resulting kinetics are not straightforward and
hamper mechanistic interpretation of the interaction in question. These unusual
kinetics include substrate activation (autoactivation), substrate inhibition,
partial inhibition, activation, differential kinetics and others. To address
this problem, several kinetic models can be proposed, based upon the assumption
that multiple substrate binding sites exist at the active site of a particular
P450, and the resulting kinetic constants are, therefore, solved to adequately
describe the observed interaction between multiple drugs. The following is an
overview of some cytochrome P450-mediated classic and atypical enzyme kinetics,
and the associated kinetic models. Applications of these kinetic models can
provide some new insights into the mechanism of P450-mediated drug-drug interactions.
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Pharmacology of Chiral Compounds:
2-Arylpropionic Acid Derivatives
M.F. Landoni and A. Soraci
Molecules exist as three dimensional structures. Therefore
they can exist in symmetrical and asymmetrical forms. Molecules with an
asymmetric centre are chiral. If the molecule and its mirror image are non-superimposable,
the relationship between the two molecules is enantiomeric and the two
stereoisomers are enantiomers. Since enantiomers have very similar or identical
physicochemical properties, it is very difficult to distinguish between them in
an achiral environment. However, once in a chiral environment, as in the body,
they exhibit clear differences. In fact, most of the physiological processes in
nature are stereospecific.
Stereospecificity can occur in pharmacokinetic processes, in
particular that utilise a carrier protein, receptor or enzyme. In addition,
stereoselectivity occurs in pharmacodynamic processes and the differences
between enantiomers can be either qualitative and quantitative.
2-arylpropionic acid derivatives (2APAs - profens) are an
important subgroup within the class of NSAIDs . These are chiral compounds
marketed as racemic mixtures. Some members of the group in an species-dependent
manner undergo a special type of metabolic transformation leading to partial
inversion to the optical antipode through a specific conjugation with CoA (coenzyme
A) and subsequent epimerization. This metabolic inversion has not only
pharmacological consequences (related to clinical effect) but also toxicological
consequences such as, formation of hybrid triglycerides and even inhibition of
fatty acid ß-oxidation.
Differences on inversion rate between compounds and species
will be discussed as well as its modification by different patho-physiologic
processes such as, inflammation.
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Pharmacodynamics of High-Dose Chemotherapy
Yago Nieto
There is usually considerable variability in anticancer drug
plasma levels when delivered at high doses requiring stem-cell support. Given
their narrow therapeutic windows and wide interpatient pharmacokinetic
variability, drug monitoring and pharmacokinetic-directed dosing represent an
attractive strategy in this setting. A major previous requirement to successful
application of therapeutic drug monitoring is identification of a significant
and clinically meaningful pharmacodynamic correlation between a pharmacokinetic
parameter and a toxic or therapeutic outcome, or preferably, both.
In this review, we will analyze the current knowledge of
identified pharmacodynamic correlations in high-dose chemotherapy. We will
summarize the observations from other authors and our own, on drugs employed at
high doses, such as cyclophosphamide, melphalan, busulfan, carmustine,
paclitaxel, or docetaxel.
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Bestatin as an Experimental Tool in Mammals
O. A. Scornik and V. Botbol
Bestatin, an antibiotic of microbial origin, is a potent
inhibitor of some, but not all aminopeptidases. It can be administered, with
low toxicity, to cultured cells, intact animals and humans. It has become a
useful tool in elucidating the physiological role of some mammalian exopeptidases
in the regulation of the immune system, in the growth of tumors and their
invasion of surrounding tissues, and in the degradation of cellular proteins.
Bestatin-sensitive enzymes play important roles in the digestion and absorption
of peptides in the brush border of the intestine and the kidney, in the
reproductive system, and in the metabolism of opioid peptides and leukotrienes.
Aminopeptidase N emerges as the major target for the effects
of bestatin on the immune system and some of its effects on tumor growth and
the endometrium. It is also the major bestatin-sensitive enzyme involved in the
degradation of oligopeptides on the surface of intestine and kidney brush borders,
and the inactivation of enkephalins in the brain. Bestatin-sensitive cytosolic
exopeptidases are important in the degradation to amino acids of di- and
tripeptides generated in most cells by cellular protein degradation, as well as
those absorbed through the brush border of intestine and kidney. Inhibition of
one of these exopeptidases, cytosol alanine aminopeptidase, results in
apoptosis. Bestatin-sensitive cystinyl aminopeptidase is abundant in placenta.
Two bestatin-sensitive enzymes, aminopeptidase B and nardilysin, are particularly
abundant in late spermatids. Finally bestatin-sensitive LTA4
hydrolase generates the potent chemotactic agent, LTB4.