Chemoreactomic analysis of magnesium- and vitamin B6-depleting drugs within the Anatomical Therapeutic Chemical classification as a basis for preventing adverse effects of pharmacotherapy

Background. Many pharmaceuticals, including antibiotics, diuretics, some antitumor agents, hormones, etc., can promote the depletion of magnesium (Mg), pyridoxine (vitamin B6, VB6), and other micronutrients (MNs) in the body. This process may lead to the development of hypomagnesemia and concomitant MN deficiencies, which are associated with a range of adverse effects, including neurotoxicity, cardiotoxicity, hepatotoxicity, etc. Moreover, the resulting micronutrient deficiency (MND) may paradoxically aggravate the underlying pathophysiological mechanisms of the diseases for which these drugs are prescribed, thereby potentially diminishing therapeutic efficacy and contributing to treatment-related complication. Objective: Chemoreactomic assessment of anti-micronutrient (anti-MN) effects of all drugs included in the Anatomical Therapeutic Chemical (ATC) classification system. Material and methods. Using modern data mining techniques, including mathematical approaches from topological data analysis, labeled graph theory (chemographs), and related method, this study performed a systematic computer-based analysis of databases describing the Mg-depleting effects of drugs; original algorithms for numerically predicting the Mg- and VB6-removing effects of drugs. Original algorithms were developed for the numerical prediction of Mg- and VB6-depleting properties of drugs, as well as for the assessment of other anti-MN effects. These algorithms were subsequently applied in a chemoreactomic screening of 2,527 drugs classified within the ATC system. Results. A database describing anti-MN properties of drugs was created for 24 MN balance indicators for 18 MNs. Algorithms for predicting the anti-MN properties of drugs were developed with a classification accuracy of 92±10% in cross-validation (the accuracy of predicting VB6 MND – 88%, Mg MND – 94-98%). On average, each drug from the ATC group accounts for 8.5±6.5 anti-MN effects. Only 100 out of 2527 (4%) drugs did not exhibit a negative impact on MN, primarily amino acids, MNs themselves, and choline drugs. The most pronounced negative impact of the drugs under study was related to the metabolism of vitamin D3 (505 ATC categories), VB6 (475 ATC categories), iron (419 ATC categories), vitamin B1 (386 ATC categories), and Mg (375 ATC categories). VB6 MND was caused by 1701 drugs, Mg MND – by 1064 drugs. Antibiotics for systemic use (ATC code J01), psycholeptics (N05) and psychoanaleptics (N06), antineoplastic agents (L01), sex hormones and modulators of the reproductive system (G03), analgesics (N02), antidepressants (N06A), diuretics (C03), antihistamines for systemic use (R06A), anti-inflammatory and antirheumatic agents (M01), direct-acting antivirals (J05A), and antiepileptic agents (N03A) were found to affect adversely the homeostasis of both Mg and VB6. A detailed description of the anti-Mg and anti-VB6 properties of these drug classes was provided. The data obtained via chemoreactomic analysis were compared with that obtained by experimental and clinical studies of Mg and VB6 preparations. Conclusion. The conducted chemoreactomic analysis provides a substantiated basis for supporting pharmacotherapy with selected medicinal preparations based on organic salts of Mg and VB6.