353
11 Computational Toxicology in Drug Discovery: Opportunities and Limitations
and on the human body. On the average the frequency of adverse drug interactions
is between 3–5 to 20 %, if patients take simultaneously from 2 to 10 drugs [70]. The
possible estimation of those interactions will increase the safety of drug therapy.
Several computational studies of drug-drug interactions depending on the molecular mechanisms of action and biotransformation pathways were performed [71,
72]. They are mainly related to the analysis of drug metabolizing enzymes, such
as isoforms of cytochrome P450, and are restricted by narrow classes of chemical
compounds.
Drug-drug interactions can be a physical (e.g., changing the pH, which depends
on the absorption of these compounds as ketoconazole and glipizide), chemical
(e.g., ciprofloxacin is a chelator of cations such as aluminum, magnesium and iron),
and biological, which depends on interactions with human proteins. The last type of
interaction is of great interest for computational predictions.
There are many mechanisms of the drug-drug interactions in humans. They may
be divided into two large groups: pharmacokinetic and pharmacodynamic drug interactions. Pharmacokinetic drug interactions include cases where one drug affects
the absorption, distribution, metabolism and excretion of another drug. Pharmacodynamic drug interactions include cases where drugs have additive or antagonistic
pharmacological effects.
11.4.1 Pharmacokinetic Drug-Drug Interactions
The key molecular mechanisms were identified during the detailed analysis of pharmacokinetic drug-drug interactions. Transport proteins play an important role for
manifestation of negative drug interactions during absorption and excretion [73].
The reason for changing the drug absorption and excretion can be the direct competition for reaction with transport protein (compounds are substrates of the same
transporter enzyme) and the influence of one drug on the activity (inhibition) or the
amount (induction of expression) of transport protein, while the other drug is a substrate of this transport protein. Therefore, the computer prediction of interaction for
chemical compounds with transporter proteins can be used to assess possible drugdrug interactions. The QSAR models for prediction of drug interaction with transporters are provided by Simulation Plus Inc. (OATP1B1 transporter), ACD/Labs (Pglycoprotein), Optibrium (P-glycoprotein). QSAR modeling for the several major
transporters including MDR1, BCRP, MRP1–4, PEPT1, ASBT, OATP2B1, OCT1,
and MCT1 was made by Sedykh with co-authors [74]. The most representative profile of interaction with transporters is calculated by PASS software (Table 11.14).
Drug distribution in the body depends on several factors: the total amount of extracellular liquid, the percentage of adipose tissue and an ability to bind with plasma
proteins, which depends on a structural formula of the compound. The last factor
plays a significant role in process of drug-drug interactions during distribution. Albumin and alpha-1 glycoprotein plasma proteins are responsible for the transfer of
major drugs and undesirable interactions between these drugs may occur due to
11 Computational Toxicology in Drug Discovery: Opportunities and Limitations
and on the human body. On the average the frequency of adverse drug interactions
is between 3–5 to 20 %, if patients take simultaneously from 2 to 10 drugs [70]. The
possible estimation of those interactions will increase the safety of drug therapy.
Several computational studies of drug-drug interactions depending on the molecular mechanisms of action and biotransformation pathways were performed [71,
72]. They are mainly related to the analysis of drug metabolizing enzymes, such
as isoforms of cytochrome P450, and are restricted by narrow classes of chemical
compounds.
Drug-drug interactions can be a physical (e.g., changing the pH, which depends
on the absorption of these compounds as ketoconazole and glipizide), chemical
(e.g., ciprofloxacin is a chelator of cations such as aluminum, magnesium and iron),
and biological, which depends on interactions with human proteins. The last type of
interaction is of great interest for computational predictions.
There are many mechanisms of the drug-drug interactions in humans. They may
be divided into two large groups: pharmacokinetic and pharmacodynamic drug interactions. Pharmacokinetic drug interactions include cases where one drug affects
the absorption, distribution, metabolism and excretion of another drug. Pharmacodynamic drug interactions include cases where drugs have additive or antagonistic
pharmacological effects.
11.4.1 Pharmacokinetic Drug-Drug Interactions
The key molecular mechanisms were identified during the detailed analysis of pharmacokinetic drug-drug interactions. Transport proteins play an important role for
manifestation of negative drug interactions during absorption and excretion [73].
The reason for changing the drug absorption and excretion can be the direct competition for reaction with transport protein (compounds are substrates of the same
transporter enzyme) and the influence of one drug on the activity (inhibition) or the
amount (induction of expression) of transport protein, while the other drug is a substrate of this transport protein. Therefore, the computer prediction of interaction for
chemical compounds with transporter proteins can be used to assess possible drugdrug interactions. The QSAR models for prediction of drug interaction with transporters are provided by Simulation Plus Inc. (OATP1B1 transporter), ACD/Labs (Pglycoprotein), Optibrium (P-glycoprotein). QSAR modeling for the several major
transporters including MDR1, BCRP, MRP1–4, PEPT1, ASBT, OATP2B1, OCT1,
and MCT1 was made by Sedykh with co-authors [74]. The most representative profile of interaction with transporters is calculated by PASS software (Table 11.14).
Drug distribution in the body depends on several factors: the total amount of extracellular liquid, the percentage of adipose tissue and an ability to bind with plasma
proteins, which depends on a structural formula of the compound. The last factor
plays a significant role in process of drug-drug interactions during distribution. Albumin and alpha-1 glycoprotein plasma proteins are responsible for the transfer of
major drugs and undesirable interactions between these drugs may occur due to