<p>Metabolite Profiling in Anticancer Drug Development: A Systematic Review</p>

Abstract

Drug metabolism is one of the most important pharmacokinetic processes and plays an important role during the stage of drug development. The metabolite profile investigation is important as the metabolites generated could be beneficial for therapy or leading to serious toxicity. This systematic review aims to summarize the research articles relating to the metabolite profile investigation of conventional drugs and herb-derived compounds for cancer chemotherapy, to examine factors influencing metabolite profiling of these drugs/compounds, and to determine the relationship between therapeutic efficacy and toxicity of their metabolites. The literature search was performed through PubMed and ScienceDirect databases up to January 2019. Out of 830 published articles, 78 articles were included in the analysis based on pre-defined inclusion and exclusion criteria. Both phase I and II enzymes metabolize the anticancer agents/herb-derived compounds. The major phase I reactions include oxidation/hydroxylation and hydrolysis, while the major phase II reactions are glucuronidation, methylation, and sulfation. Four main factors were found to influence metabolite formation, including species, gender, and route and dose of drug administration. Some metabolites were identified as active or toxic metabolites. This information is critical for cancer chemotherapy and anticancer drug development.

Metabolism-Guided Optimization of Tryptophanol-Derived Isoindolinone p53 Activators

“…Glucuronidation is a key contributor for decreased drug bioavailability, by excretion [ 34 , 35 ]. To evaluate the ability of ( S )-tryptophanol-derived isoindolinones to undergo this Phase II pathway, additional incubations were performed in alamethicin induced-HLM in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and uridine diphosphate glucuronic acid (UDPGA) co-factors [ 34 ].…”

Chemotherapeutic and Safety Profile of a Fraction from Mimosa caesalpiniifolia Stem Bark

“…The cytotoxic activity on cancer cells using in vitro models may not reflect in vivo findings, since the latter considers pharmacokinetic and pharmacodynamic variables, such as ligand binding to specific receptors, downstream cascade, involvement of second messengers, water/lipid solubility, bioavailability, first-pass metabolism, and renal excretion [ 57 , 58 ]. Therefore, combining these two types of scientific tools is appropriate for a more complete assessment of a substance with antiproliferative action.…”

“…The development of new (phyto)pharmaceutical products includes not only pharmacodynamic discoveries but also essential data about the pharmacokinetics profile, therapeutic window, and pharmacological safety, including systemic and genetic toxicology [ 58 , 59 ]. These assessments allow the exclusion of undesirable drug candidates and save time, material and human resources.…”

Anticancer Potentials of the Lignan Magnolin: A Systematic Review

“…The researchers found that the PKs of magnolin were not affected by the dosage, regardless of whether it was administered intravenously or orally [164]. The process of drug metabolism is a critical aspect of pharmacokinetics and plays a significant role in drug development [165]. Studies have shown that in rats, magnolin undergoes metabolism to produce 4'-O-desmethyl magnolin, 4"-O-desmethyl magnolin, and their respective glucuronides [166].…”