356
A. Zakharov and A. Lagunin
rates, carbamazepine, glyutetimid, griseofulvin, primidone, finitoin, rifabutin,
rifampin and troglitazone. Some drugs, as ritonavir, may act both inducers of
enzymes and their inhibitors. It is considered that drugs metabolized by CYP3A4
and CYP2A9 are especially sensitive to enzyme induction.
4. The enzyme induction may increase toxic metabolites because of some drugs
are transformed into toxic metabolites. For example, analgesic acetaminophen
is mainly converted into non-toxic metabolites, but its small amount is transformed by CYP2E1 into a cytotoxic metabolite N-acetyl-p-benzoquinone imine.
Enzyme inductors may increase the formation of toxic metabolite and increase
the risk of hepatotoxicity and damage of other organs.
Obviously, it is necessary to create models to predict an interaction of compounds
with the most important drug metabolizing enzymes and to develop an algorithm
for analyzing results of these predictions. QSAR models for estimation of drug interactions with drug-metabolizing enzymes are provided by Simulation Plus, ACD/
Labs, GeneXplain, Accelris, Optibrium, Lhasa and Multicase. The excellent review
of software and in silico methods for evaluation of possible ligand interactions with
drug-metabolizing enzymes and prediction of possible metabolites was recently
published [78].
11.4.2 Pharmacodynamic Drug Interactions
Pharmacodynamic drug interactions include the cases where drugs show additive or
antagonistic pharmacodynamic effects.
1. Antagonistic pharmacodynamic effects. This group of interactions includes
the cases where drugs have the opposite pharmacodynamic effects, leading to a
decrease in the exposure of one or both drugs. For example, compounds, which
have a tendency to increase the blood pressure (as a non-steroidal anti-inflammatory compound), can inhibit an antihypertensive effect of angiotensin-converting enzyme inhibitors. Decrease of benzodiazepine effects by theophylline
is another example.
2. Additive pharmacodynamic effects. In the case when two or more drugs exhibit
similar pharmacodynamic effects it may produce an excessive manifestation of
toxicity. It could be compounds whose combination may cause QT interval prolongation, leading to ventricular arrhythmia, as well as compounds that increase
the concentration of potassium in blood and lead to hyperkalemia. An additive
pharmacodynamic effect is also used for therapeutic purposes, so diuretics and
angiotensin-converting enzyme inhibitors cause the blood pressure reduction.
To reveal these types of interaction, different types of prediction results are required.
It is necessary to take into account the interaction of compounds with proteins, as
well as information on the relationship between molecular mechanisms of action
and biological effects. This analysis can be done with a computer program PASS
(Prediction of the Activity Spectrum of Substance) and PharmaExpert (analysis of
A. Zakharov and A. Lagunin
rates, carbamazepine, glyutetimid, griseofulvin, primidone, finitoin, rifabutin,
rifampin and troglitazone. Some drugs, as ritonavir, may act both inducers of
enzymes and their inhibitors. It is considered that drugs metabolized by CYP3A4
and CYP2A9 are especially sensitive to enzyme induction.
4. The enzyme induction may increase toxic metabolites because of some drugs
are transformed into toxic metabolites. For example, analgesic acetaminophen
is mainly converted into non-toxic metabolites, but its small amount is transformed by CYP2E1 into a cytotoxic metabolite N-acetyl-p-benzoquinone imine.
Enzyme inductors may increase the formation of toxic metabolite and increase
the risk of hepatotoxicity and damage of other organs.
Obviously, it is necessary to create models to predict an interaction of compounds
with the most important drug metabolizing enzymes and to develop an algorithm
for analyzing results of these predictions. QSAR models for estimation of drug interactions with drug-metabolizing enzymes are provided by Simulation Plus, ACD/
Labs, GeneXplain, Accelris, Optibrium, Lhasa and Multicase. The excellent review
of software and in silico methods for evaluation of possible ligand interactions with
drug-metabolizing enzymes and prediction of possible metabolites was recently
published [78].
11.4.2 Pharmacodynamic Drug Interactions
Pharmacodynamic drug interactions include the cases where drugs show additive or
antagonistic pharmacodynamic effects.
1. Antagonistic pharmacodynamic effects. This group of interactions includes
the cases where drugs have the opposite pharmacodynamic effects, leading to a
decrease in the exposure of one or both drugs. For example, compounds, which
have a tendency to increase the blood pressure (as a non-steroidal anti-inflammatory compound), can inhibit an antihypertensive effect of angiotensin-converting enzyme inhibitors. Decrease of benzodiazepine effects by theophylline
is another example.
2. Additive pharmacodynamic effects. In the case when two or more drugs exhibit
similar pharmacodynamic effects it may produce an excessive manifestation of
toxicity. It could be compounds whose combination may cause QT interval prolongation, leading to ventricular arrhythmia, as well as compounds that increase
the concentration of potassium in blood and lead to hyperkalemia. An additive
pharmacodynamic effect is also used for therapeutic purposes, so diuretics and
angiotensin-converting enzyme inhibitors cause the blood pressure reduction.
To reveal these types of interaction, different types of prediction results are required.
It is necessary to take into account the interaction of compounds with proteins, as
well as information on the relationship between molecular mechanisms of action
and biological effects. This analysis can be done with a computer program PASS
(Prediction of the Activity Spectrum of Substance) and PharmaExpert (analysis of