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Drug metabolites and their effects on the development of adverse reactions: Revisiting Lipinski’s Rule of Five

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Abstract

Many studies have shown that toxicities of anticancer drugs and their adverse effects are related to their chemical structure and high molecular weight that may result in a number of metabolites interacting with drug off-target networks. These factors require further attention for advancing cancer treatment and decreasing toxicities caused by the molecular complexity of antineoplastic agents. Providing more target-selective and tolerable cancer therapy with fewer side effects would not only improve patients’ compliance, but also would decrease cancer-remission rates. This review presents several antineoplastic agents and their metabolites with molecular weights greater than 500 g/mol, which reportedly cause more than fifteen types of adverse reactions during breast cancer therapy.

Introduction

Adverse drug reactions (ADRs) are one of the main concerns in the pharmaceutical research and drug development, as they may result in treatment failures and removal of drugs from the market. ADRs can be caused by factors related to either drug, or individual patient characteristics. In respect with drugs, these reactions can be triggered by a variety of factors, such as the dosage, drug formulation, route of administration, drug-drug interactions (DDI), drug-food interactions, drug metabolism, and allergic or hypersensitivity reactions that affect the immunologic system (Cho and Uetrecht, 2017, Fliri et al., 2005, Park et al., 1998).

Drug transporters and their role in DDI during chemotherapy regimens display a significant role in the development of ADRs (Glaeser, 2011, Mealey and Fidel, 2015, Segal et al., 2014). P-glycoprotein is a drug transporter belonging to the ABC transporter family. This family of transmembrane proteins promotes the removal of drugs from the cell. A wide variety of drugs are considered to be substrates of P-gp, as P-gp possesses the ability to target a great number of drugs despite their molecular size and hydrophobic character. P-gp transporters are expressed in many different tissues, including hepatic, renal, intestinal, and the blood-brain barrier (Lin and Yamazaki, 2003). Due to their lack of drug specificity and high expression throughout the body, P-gp transporters are likely to compromise the absorption and metabolism of many drugs. This in turn is likely to influence the bioavailability and toxicity of drugs. Moreover, P-gp transporters are also involved in many DDI. When drugs that are substrates, inhibitors, or inducers of P-gp are taken concurrently, DDI are likely to occur. DDI are often observed during cancer therapy as patients take multiple drugs to alleviate the ADRs caused by this type of treatment (Lin and Yamazaki, 2003). When DDI occur during chemotherapy, the bioavailability of an anticancer drug that is substrate of P-gp can decrease if taken along with an inducer of P-gp. This can likely compromise the effectiveness of the treatment. On the other hand, if an inhibitor of P-gp is taken, the bioavailability of the anticancer drug increases, thus enhancing the likelihood of drug toxicity (Glaeser, 2011). ADRs may also be considered as a patient-related factor, that depend on the patient’s age, sex, genetic variability, physical conditions, and other similar factors (Fliri et al., 2005, Nicolson et al., 2010). Therefore, ADRs are related to both the physicochemical properties of the drug (PPD) and the patient’s individual characteristics. Furthermore, PPD including the complexity of the molecular drug structures, their molecular weight (MW), and their hydrophobicity can fairly predict the pharmacokinetics (PK) and pharmacodynamic (PD) process and account for the development of ADRs.

It is well known that drugs, especially anticancer drugs, do not only affect cancerous cells, but also attack healthy cells. Their metabolism can cause many off-target events during and post-chemotherapy (Dobbelstein and Moll, 2014). The most common short-term ADRs include nausea, vomiting, diarrhea, alopecia, fatigue, anemia, neutropenia, and neuropathy (Flynn et al., 2017, Krukiewicz and Zak, 2016, Society, A.C., 2016, Tao et al., 2015). The long-term chronic effects of chemotherapy are usually more complicated and life-threatening. These commonly include cardiomyopathy, neurocognitive dysfunction, posterior cancers, and psychological disorders (Society, A.C., 2016, Tao et al., 2015).

A recent study showed that breast cancer (BC) was the most common type of cancer in the United States in 2016 (Smith et al., 2016). Despite a high survival rate of 89% (Society, 2016), it is the second most common cause of death from cancer among American women (Smith et al., 2016). There are multiple factors involved with choosing the appropriate drug treatment for BC, such as the presence of progesterone or estrogen receptors, the size of the tumor, and the number of lymph nodes involved (Society, 2016). Regardless of the stage of the disease, the majority of patients diagnosed with BC undergo chemotherapy treatment (Society, 2016). Adjuvant therapy is often used to treat BC, a process in which the chemotherapy is administered in concomitance with another anticancer drug to increase the efficacy of the treatment. Regardless of the drug(s) chosen or the duration of treatment, chemotherapy is very likely to cause numerous unpleasant ADRs.

Section snippets

Physicochemical properties of drugs

ADRs are strongly related to the physicochemical properties of drugs (PPD). The differences in the PPD can regulate the mechanism of drugs absorption, distribution, efficacy, metabolism and excretion (ADME) of these compounds inside the body. Moreover, these differences are also often correlated with drug promiscuity (DP) (Haupt et al., 2013, Tarcsay and Keseru, 2013), and the “Rule of Five” (RO5) developed by Lipinski (Lipinski et al., 2001). Thus, DP is usually related with compounds with

Active metabolites

Administration of drugs by IV route achieves a higher bioavailability than oral administration. Drugs administered by IV route are directly and rapidly delivered to the bloodstream, thus obtaining the maximum bioavailability rate (Terwogt et al., 1999a). On the other hand, orally administered drugs first need to be released from their formulation to reach the Gastrointestinal tract (GIT) and then be absorbed by the bloodstream. During this lengthy process, the oral drug can also meet

Breast cancer drugs with high molecular weight

This review presents the most commonly used Breast Cancer (BC) drugs with MW greater than 500 g/mol. The most recent research reports on these drugs were explored to understand their interactions with the desired target receptors and how the metabolism of drugs possessing larger structures may be linked to their ADRs.

There are nearly 490 ADRs of the BC drugs that occur during chemotherapy (Dobbelstein and Moll, 2014, Flynn et al., 2017, Krukiewicz and Zak, 2016). The main focus of this study is

Conclusion

This review looked into eight breast cancer drugs with large and complex chemical structures that also cause common ADRs during chemotherapy. The drugs were chosen due to their MW (greater than 500 g/mol), and structural features that are in disagreement with Lipinski’s RO5 criteria (Lipinski et al., 2001). Their MW varied from 506.70 g/mol (IXA) to as high as 1269.43 g/mol (GOSE). It is also known that seven of the anticancer drugs have polar surface areas higher than 140 Å, a limit defined by

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