Antioxidant; Nrf-2/HO-1; Microbial Metabolite; Endogenous Metabolite

By lowering ROS levels, downregulating cytoplasmic Nrf2 expression, and upregulating whole-cell HO-1 expression, pyridoxine demonstrates its protective potential against AD [1].
Pyridoxine is a water- soluble pyridine derivative. The effect of pyridoxine in cell models of Alzheimer's disease (AD), and the potential mechanisms involved, are not fully understood. In this study, the anti-AD effects of pyridoxine were studied in an AD cell model using a combination of techniques viz MTT assay, western blotting and assays for reactive oxygen species (ROS). Assays were also carried out to determine the mechanism underlying the antioxidant effects of pyridoxine. The results obtained revealed that pyridoxine exerted a protective potential against AD, attenuated ROS levels, decreased the expressions of cytoplasmic Nrf2, and upregulated whole-cell HO-1 expression. These results suggest that the anti-AD effect of pyridoxine may be attributed to its anti-oxidant property elicited via stimulation of the Nrf2/HO-1 pathway [1].

Objective: Linezolid is often used to treat antibacterial-resistant infections. Linezolid can cause side effects. To date, the effectiveness of the simultaneous administration of pyridoxine and linezolid is unclear. Here we investigate the protective effect of pyridoxine on linezolid-induced hematological toxicity, hepatotoxicity, and oxidative stress in rats.
Material and methods: The 40 male pediatric Spraque-Dawley rats were separated into 4 groups: control, linezolid, pyridoxine, and linezolid-pyridoxine. A complete blood count, liver function test, and measurements of antioxidant enzyme activities for superoxide dismutase, glutathione peroxidase, catalase, and lipid peroxidation were performed in blood before treatment and 2 weeks after administration of the treatment.
Results: White blood cell and hemoglobin counts for the linezolid group decreased, and the alanine aminotransferase level in the linezolid group increased compared to their respective baseline values. Post-treatment white blood cell decreased in the linezolid and linezolid- pyridoxine groups compared to those in the control group (P < .001). Alanine aminotransferase levels increased in the linezolid and linezolid-pyridoxine groups compared to those in the control group (P < .001 and P < .05, respectively). The activity of superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde levels increased in the linezolid group compared to the control group (P < .001, P < .05, P < .001, and P < .001, respectively). Linezolid plus pyridoxine treatment caused a significant decrease in malondialdehyde levels and superoxide dismutase, catalase, and glutathione peroxidase enzyme activities compared to the linezolid group (P < .001, P < .01, P < .001, and P < .01, respectively).
Conclusion: pyridoxine may be an effective adjuvant agent for the prevention of linezolid toxicity in rat models [2].

Forty male pediatric Spraque–Dawley rats (8 weeks old, weighing 200-250 g) were divided into 4 groups: control (C, n = 10), linezolid (L, n = 10), pyridoxine (P, n = 10), and linezolid plus pyridoxine (LP, n = 10). For 14 days, by gavage twice a day, 1 mL of saline solution was administered to the C group. In addition, 125 mg/kg/day of linezolid was administered to the L group;100 mg/kg/day of pyridoxine was administered to the P group, and 125 mg/kg/day of linezolid and 100 mg/kg/day of pyridoxine to the LP group.

Absorption, Distribution and Excretion
The B vitamins are readily absorbed from the gastrointestinal tract, except in malabsorption syndromes. Pyridoxine is absorbed mainly in the jejunum. The Cmax of pyridoxine is achieved within 5.5 hours.
The major metabolite of pyridoxine, 4-pyridoxic acid, is inactive and is excreted in urine
Pyridoxine main active metabolite, pyridoxal 5’-phosphate, is released into the circulation (accounting for at least 60% of circulating vitamin B6) and is highly protein bound, primarily to albumin.

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Metabolism / Metabolites
Pyridoxine is a prodrug primarily metabolized in the liver. The metabolic scheme for pyridoxine is complex, with formation of primary and secondary metabolites along with interconversion back to pyridoxine. Pyridoxine's major metabolite is 4-pyridoxic acid.
Hepatic.
Half Life: 15-20 days

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Biological Half-Life
The total adult body pool consists of 16 to 25 mg of pyridoxine. Its half-life appears to be 15 to 20 days.

Toxicity Summary
Vitamin B6 is the collective term for a group of three related compounds, pyridoxine (PN), pyridoxal (PL) and pyridoxamine (PM), and their phosphorylated derivatives, pyridoxine 5'-phosphate (PNP), pyridoxal 5'-phosphate (PLP) and pyridoxamine 5'-phosphate (PMP). Although all six of these compounds should technically be referred to as vitamin B6, the term vitamin B6 is commonly used interchangeably with just one of them, pyridoxine. Vitamin B6, principally in its biologically active coenzyme form pyridoxal 5'-phosphate, is involved in a wide range of biochemical reactions, including the metabolism of amino acids and glycogen, the synthesis of nucleic acids, hemogloblin, sphingomyelin and other sphingolipids, and the synthesis of the neurotransmitters serotonin, dopamine, norepinephrine and gamma-aminobutyric acid (GABA).

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Toxicity Data
LD50: 4 gm/kg (oral, rat)

[1]. Pyridoxine exerts antioxidant effects in cell model of Alzheimer's disease via the Nrf-2/HO-1 pathway. Cell Mol Biol (Noisy-le-grand). 2018 Jul 30;64(10):119-124.

[2]. The Protective Effects of Pyridoxine on Linezolid-Induced Hematological Toxicity, Hepatotoxicity, and Oxidative Stress in Rats. Turk Arch Pediatr. 2023 May;58(3):298-301.

Pharmacodynamics
Vitamin B6 (pyridoxine) is a water-soluble vitamin used in the prophylaxis and treatment of vitamin B6 deficiency and peripheral neuropathy in those receiving isoniazid (isonicotinic acid hydrazide, INH). Vitamin B6 has been found to lower systolic and diastolic blood pressure in a small group of subjects with essential hypertension. Hypertension is another risk factor for atherosclerosis and coronary heart disease. Another study showed pyridoxine hydrochloride to inhibit ADP- or epinephrine-induced platelet aggregation and to lower total cholesterol levels and increase HDL-cholesterol levels, again in a small group of subjects. Vitamin B6, in the form of pyridoxal 5'-phosphate, was found to protect vascular endothelial cells in culture from injury by activated platelets. Endothelial injury and dysfunction are critical initiating events in the pathogenesis of atherosclerosis. Human studies have demonstrated that vitamin B6 deficiency affects cellular and humoral responses of the immune system. Vitamin B6 deficiency results in altered lymphocyte differentiation and maturation, reduced delayed-type hypersensitivity (DTH) responses, impaired antibody production, decreased lymphocyte proliferation and decreased interleukin (IL)-2 production, among other immunologic activities.

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We observed a significant increase in antioxidant enzyme activity and MDA levels in erythrocytes for rats treated with linezolid. Previous studies have shown that antioxidant enzyme activities generally decrease after oxidative damage. However, in our study, MDA levels and antioxidant enzyme activities were increased after the administration of linezolid. This suggested that the antioxidant system was activated to remove free radicals from linezolid. Although membrane damage occurs in erythrocytes, the lack of adequate hemoglobin levels was attributed to the absence of hemolysis. On the other hand, both antioxidant enzymes and MDA levels were not elevated in L and LP groups. These changes induced by pyridoxine have been shown to decrease the free radical production due to linezolid and/or free radicals formed by the help of pyridoxine. The addition of pyridoxine to protect against the side effects of linezolid used in the treatment of gram-positive bacterial infections should be recommended to increase the effectiveness of treatment and prevent complications. Since the hematological toxic effects of linezolid limit its use against multidrug-resistance gram-positive pathogens, we believe that this study will be promising to guide future research. [2]

C8H11NO3

169.1778

169.073

C, 56.80; H, 6.55; N, 8.28; O, 28.37

65-23-6

Pyridoxine-d5;688302-31-0;Pyridoxine hydrochloride;58-56-0

1054

White to off-white solid powder

1.4±0.1 g/cm3

491.9±40.0 °C at 760 mmHg

159-162ºC

251.3±27.3 °C

0.0±1.3 mmHg at 25°C

1.621

-1.1

3

4

2

12

142

0

LXNHXLLTXMVWPM-UHFFFAOYSA-N

InChI=1S/C8H11NO3/c1-5-8(12)7(4-11)6(3-10)2-9-5/h2,10-12H,3-4H2,1H3

4,5-bis(hydroxymethyl)-2-methylpyridin-3-ol

pyridoxine; 65-23-6; Pyridoxol; Pyridoxin; 3-hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridine; Adermine; Gravidox; Hydoxin;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~591.09 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (12.29 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (12.29 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (12.29 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)