Human Endogenous Metabolite; Microbial Metabolite

Adenine nucleosides act on four G protein-coupled receptors: one of them, A1 and A3, is mainly coupled to the Gi family G proteins; two of them, A2A and A2B, are mainly coupled to G proteins. These receptors include coffee Antagonist due to entrance of xanthine. Through these receptors, it affects many cells and organs, often with cytoprotective functions [2]. Adenosine is an extracellular signaling molecule generated from its precursor molecules 5'-adenosine triphosphate (ATP)) and 5'-adenosine monophosphate (AMP) [3]. Adenosine is a common metabolite of ATP that exhibits cytotoxic effects at high concentrations. Adenosine (1.0- 4.0 mM; 12-24 hours) inhibits cell viability and triggers endoplasmic reticulum depletion in HepG2 cells [4]. Adenosine induces a variety of phosphates. Adenosine (2.0 mM; 12-24 hours) Induces freedom in HepG2 cells In the HepG2 cell line, successful adenosine-induced activation of AMPK/mTOR partially blocks the ER and reduces inactivated cell death [4].

Absorption, Distribution and Excretion
Data regarding the absorption of adenosine are not readily available.
Adenosine is predominantly eliminated in the urine as uric acid.
Data regarding the volume of distribution of adenosine are not readily available.
Data regarding the clearance of adenosine are not readily available.
Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical.
As Adenocard requires no hepatic or renal function for its activation or inactivation, hepatic and renal failure would not be expected to alter its effectiveness or tolerability.

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Metabolism / Metabolites
Adenosine can be phosphorylated by adenosine kinase to form adenosine monophosphate. From there, it is phosphorylated again by adenylate kinase 1 to form adenosine diphosphate, and again by nucleoside diphosphate kinase A or B to form adenosine triphosphate. Alternatively, adenosine can be deaminated by adenosine deaminase to form inosine. Iosine is phosphorylated by purine nucleoside phosphorylase to form hypoxanthine. Hypoxanthine undergoes oxidation by xanthine dehydrogenase twice to form the metabolites xanthine, followed by uric acid.
Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower Km and Vmax than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway.
Adenosine is rapidly metabolized intracellularly to the inactive metabolites adenosine monophosphate and inosine ... The drug is cleared by cellular uptake, principally by erythrocytes and vascular endothelial cells, via a specific transmembrane nucleoside transport system.
Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid.
Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. While extracellular adenosine is primarily cleared by cellular uptake, ... excessive amounts may be deaminated by an ecto-form of adenosine deaminase.
Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol.
Half Life: Less than 10 secs

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Biological Half-Life
The half life of adenosine in blood is less than 10 seconds.
... The plasma half-life of adenosine is less than 10 seconds.

Toxicity Summary
Adenosine slows conduction time through the AV node and can interrupt the reentry pathways through the AV node, resulting in the restoration of normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White Syndrome. This effect may be mediated through the drug's activation of cell-surface A₁ and A₂ adenosine receptors. Adenosine also inhibits the slow inward calcium current and activation of adenylate cyclase in smooth muscle cells, thereby causing relaxation of vascular smooth muscle. By increasing blood flow in normal coronary arteries with little or no increase in stenotic arteries (with little to no increase in stenotic arteries), adenosine produces a relative difference in thallous (thallium) chloride TI 201 uptake in myocardium supplied by normal verus stenotic coronary arteries.

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Protein Binding
Adenosine is bound to albumin in plasma, however data regarding the extent of binding are not readily available.

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Interactions
The effects of adenosine are antagonized by methylxanthines such as caffeine and theophylline. In the presence of these methylxanthines, larger doses of adenosine may be required or adenosine may not be effective.
Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of adenosine may be effective in the presence of dipyridamole.
Carbamazepine has been reported to increase the degree of heart block produced by other agents. As the primary effect of adenosine is to decrease conduction through the A-V node, higher degrees of heart block may be produced in the presence of carbamazepine.

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Non-Human Toxicity Values
LD50 Mouse ip 500 mg/kg

[1]. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ. 2007;14(7):1315-1323.

[2]. Pharmacology of Adenosine Receptors: The State of the Art. Physiol Rev. 2018;98(3):1591-1625.

[3]. Adenosine: an old drug newly discovered. Anesthesiology. 2009;111(4):904-915.

[4]. Inhibition of autophagy enhances adenosine induced apoptosis in human hepatoblastoma HepG2 cells. Oncol Rep. 2019;41(2):829-838.

Therapeutic Uses
Analgesics; Anti-Arrhythmia Agents; Vasodilator Agents
Intravenous Adenocard (adenosine injection) is indicated for conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT), including that associated with accessory bypass tracts (Wolff-Parkinson-White Syndrome). When clinically advisable, appropriate vagal maneuvers (eg, Valsalva maneuver), should be attempted prior to Adenocard administration. /Included in US product label/
Adenocard does not convert atrial flutter, atrial fibrillation, or ventricular tachycardia to normal sinus rhythm. In the presence of atrial flutter or atrial fibrillation, a transient modest slowing of ventricular response may occur immediately following Adenocard administration.
Intravenous Adenoscan is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately. /Included in US product label/
/Experimental Therapy:/ ... It has been shown that, in Japanese men, adenosine improves androgenetic alopecia due to the thickening of thin hair due to hair follicle miniaturization. To investigate the efficacy and safety of adenosine treatment to improve hair loss in women, 30 Japanese women with female pattern hair loss were recruited for this double-blind, randomized, placebo-controlled study. Volunteers used either 0.75% adenosine lotion or a placebo lotion topically twice daily for 12 months. Efficacy was evaluated by dermatologists and by investigators and in phototrichograms. As a result, adenosine was significantly superior to the placebo according to assessments by dermatologists and investigators and by self-assessments. Adenosine significantly increased the anagen hair growth rate and the thick hair rate. No side-effects were encountered during the trial. Adenosine improved hair loss in Japanese women by stimulating hair growth and by thickening hair shafts. Adenosine is useful for treating female pattern hair loss in women as well as androgenetic alopecia in men.

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Drug Warnings
Contraindications include known hypersensitivity to adenosine, second- or third-degree AV block (except in patients with a functioning artificial pacemaker), sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker), and known or suspected bronchoconstrictive or bronchospastic lung disease (eg, asthma).
Following iv injection of adenosine, new arrhythmias (ventricular premature complexes [VPCs], atrial premature complexes, atrial fibrillation, sinus bradycardia, sinus tachycardia, skipped beats, and varying degrees of AV nodal block) frequently appear at the time of conversion to normal sinus rhythm. These arrythmias generally last only a few seconds and resolve without intervention. However, transient or prolonged episodes of asystole, sometimes fatal, have been reported with iv injection of adenosine. Ventricular fibrillation has been reported rarely with iv injection of the drug, including both resuscitated and fatal events. In most cases, these adverse effects occurred in patients receiving concomitant therapy with digoxin or, less frequently, digoxin and verapamil, although a causal relationship has not been established.
Some clinicians state that adenosine should not be used in patients with wide-complex tachycardias of unknown origin because of the risk of inducing potentially serious arrhythmias, including atrial fibrillation with a rapid ventricular rate or prolonged asystole with severe hypotension in preexcited tachycardias (eg, atrial flutter); the drug also may induce ventricular fibrillation in patients with severe coronary artery disease.
Appropriate resuscitative measures should be readily available.
For more Drug Warnings (Complete) data for Adenosine (16 total), please visit the HSDB record page.

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Pharmacodynamics
Adenosine is indicated as an adjunct to thallium-201 in myocardial perfusion scintigraphy and also indicated for conversion of sinus rhythm of paroxysmal supraventricular tachycardia. Adenosine has a short duration of action as the half life is <10 seconds, and a wide therapeutic window. Patients should be counselled regarding the risk of cardiovascular side effects, bronchoconstriction, seizures, and hypersensitivity.

C10H13N5O4

267.2413

267.096

C, 44.94; H, 4.90; N, 26.21; O, 23.95

58-61-7

Adenosine-13C5; 159496-13-6; (R)-3-Hydroxybutanoic acid-13C2 sodium; 202114-54-3; Adenosine-1′-13C; 201996-55-6; Adenosine-13C; 54447-57-3; Adenosine-d2; 82741-17-1; Adenosine 5'-diphosphate disodium; 16178-48-6; Adenosine-d; 109923-50-4; Adenosine-15N5; 168566-57-2; Adenosine-2′-13C; 714950-52-4; Adenosine-3′-13C; 714950-53-5; Adenosine-d-1; 119540-53-3; Adenosine-d-2; Adenosine-13C10,15N5; 202406-75-5

60961

White to off-white solid powder

2.1±0.1 g/cm3

676.3±65.0 °C at 760 mmHg

234-236ºC

362.8±34.3 °C

0.0±2.2 mmHg at 25°C

1.907

-1.02

4

8

2

19

335

4

O1[C@]([H])(C([H])([H])O[H])[C@]([H])([C@]([H])([C@]1([H])N1C([H])=NC2=C(N([H])[H])N=C([H])N=C12)O[H])O[H]

OIRDTQYFTABQOQ-KQYNXXCUSA-N

InChI=1S/C10H13N5O4/c11-8-5-9(13-2-12-8)15(3-14-5)10-7(18)6(17)4(1-16)19-10/h2-4,6-7,10,16-18H,1H2,(H2,11,12,13)/t4-,6-,7-,10-/m1/s1

(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol

NSC627048; NSC-627048; Adenosine; NSC 627048

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: 27~33.3 mg/mL (101.0~124.7 mM)

Solubility in Formulation 1: 6.67 mg/mL (24.96 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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