Cellular enzymes transform didanosine into dideoxyadenosine triphosphate (dd-ATP), a potent antiviral metabolite with an intracellular half-life that ranges from 8 to 24 hours[1]. Didanosine exhibits antiretroviral action against HIV infection, with an IC50 value of 0.24–0.6 mg/L[3]. In IEC-6 cells, didanosine (5, 10, 50, and 100 ug/ml; 24 and 48 hours) does not significantly reduce cell proliferation[2].

For seven days, mice given didanosine (100, 150 mg/kg; po) have shorter duodenal and jejunal villus[2].

Cell Proliferation Assay[2]
Cell Types: IEC-6 cells
Tested Concentrations: 5, 10, 50, 100 ug/ml
Incubation Duration: 24, 48 h
Experimental Results: Did not show any significant inhibition of cell proliferation at either 24 h or 48 h.

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Apoptosis Analysis[2]
Cell Types: IEC-6 cells
Tested Concentrations: 100 ug/ml
Incubation Duration: 24 h
Experimental Results: Induced apoptosis with the apoptosis rates of 4.7% to 7.4%.

Animal/Disease Models: 30-40 g, male swiss mice[2]
Doses: 100, 150 mg/kg
Route of Administration: Po; daily for 7 days
Experimental Results: Caused significant reductions in duodenal and in jejunal villus length and Dramatically diminished ileal crypt depth.

Absorption, Distribution and Excretion
Rapidly absorbed (bioavailability 30-40%) with peak plasma concentrations appearing within 0.5 and 1.5 hrs.
Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. Purines are eliminated by the kidneys.
A single oral dose of 375 mg didanosine was administered to two pregnant women (length of amenorrhoea, 21 and 24 weeks). Maternal blood was collected by venepuncture, and amniotic fluid and fetal blood samples were taken 65 and 78 min after treatment. Didanosine crossed the placenta, with fetal:maternal ratios of 0.14 and 0.19.
Presence of food in the GI tract generally decreases the rate and extent of absorption of oral didanosine. If didanosine delayed-release capsules are administered with food, peak plasma concentrations and AUC of the drug are decreased approximately 46 and 19%, respectively. In one study, the bioavailability of chewable/dispersible, buffered tablets of didanosine administered up to 30 minutes prior to a meal was similar to the drug's bioavailability under fasting conditions. When the tablets were administered up to 2 hours after a meal, peak plasma concentrations and AUC of didanosine were decreased approximately 55%.
Antacids increase the oral bioavailability of didanosine.
Didanosine is rapidly, but incompletely, absorbed following oral administration, and peak plasma concentration of the drug generally are attained within 0.25-1.5 hr following administration of a single dose of the drug given as chewable/dispersible, buffered tablets or buffered powder for oral solution. Bioavailability of didanosine given as chewable/dispersible, buffered tablets is about 20-25% greater than the bioavailability of the drug given as an oral solution prepared from the buffered powder, and the pharmacokinetics following a 200 mg dose of chewable/dispersible, buffered tablets are approximately equivalent to those following a 250 mg dose of the buffered powder for oral solution.
For more Absorption, Distribution and Excretion (Complete) data for DIDEOXYINOSINE (17 total), please visit the HSDB record page.

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Metabolism / Metabolites
Rapidly metabolized intracellularly to its active moiety, 2,3-dideoxyadenosine-5-triphosphate (ddA-TP). It is then further metabolized hepatically to yield hypoxanthine, xanthine, and uric acid.
The metabolic fate of didanosine has not been fully evaluated in humans; however, because didanosine is an analog of inosine, a naturally occurring purine nucleoside, metabolism of the drug presumably would occur via the same pathways responsible for the elimination of endogenous purines.
Intracellularly, didanosine is converted to dideoxyinosine-5'-monophosphate. ...The monophosphate derivative may then be aminated to dideoxyadenosine-5'-monophosphate in a reaction catalysed by adenylosuccinate synthetase/lyase and phosphorylated to dideoxyadenosine-5'-diphosphate and to dideoxyadenosine-5'-triphosphate via other enzymes (eg, purine nucleoside monophosphate /kinase/, purine /nucleoside/ diphosphate kinase). Intracellular (host cell) conversion of didanosine to triphosphate derivative is necessary for the antiviral activity of the drug.
Didanosine is metabolized along two pathways. A quantitatively minor pathway that is responsible for the antiretroviral activity of the drug involves phosphorylation and reversible amination of didanosine monophosphate to dideoxyadenosine monophosphate through the action of adenylosuccinate synthetase and adenylosuccinate lyase. The dideoxyadenosine monophosphate is further phosphorylated to the triphosphate (ddATP) by purine nucleoside monophosphate kinase and purine nucleoside diphosphate kinase. The intracellular half-time of ddATP is 1224 hr, suggesting that less frequent dosing may be required than with zidovudine or zalcitabine. In addition to inhibiting the viral reverse transcriptase, ddATP becomes incorporated into DNA and terminates the replicating DNA chain in both cellular and viral DNA. Although dideoxyadenosine phosphorylation is critical to the mechanism of antiviral activity, it is responsible for only a small fraction of the total drug disposition. Approximately 40% of the total dose is recovered as unchanged drug in the urine, about 50% as hypoxanthine and about 4% as uric acid, while non-renal clearance occurs via metabolism and/or biliary excretion. The major metabolic pathway involves metabolism to uric acid through purine nucleotide phosphorylase, which produces hypoxanthine. This compound either re-enters the purine nucleotide pools or is further metabolized to xanthine and uric acid through the action of xanthine oxidase.

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Biological Half-Life
30 minutes in plasma and more than 12 hours in intracellular environment.
In adults with HIV infection, the plasma half-life of didanosine averages 0.97-1.6 hr (range: 0.3-4.64 hr). In children and adolescents with HIV infections, the plasma half-life averages 0.8 hr (range 0.51-1.2 hr).

Interactions
The absorption of ciprofloxacin is dramatically reduced when it is coadministered with didanosine. This interaction is caused by complexation between the magnesium and aluminum cations and the ciprofloxacin molecule, which results in the formation of a nonabsorbable complex.
The antiretroviral effects of didanosine and zidovudine are synergistic against HIV-1 (strain HTLV-IIIB) when tested in vitro in MT-4 cells, peripheral blood lymphocytes, and macrophages.
Although the clinical importance is unclear, some patients with HIV infections receiving ... triazolam and didanosine reportedly became confused while the drugs were administered concomitantly; the confusion resolved when both drugs were discontinued and did not recur when didanosine therapy was reinitiated alone. Confusion can occur with benzodiazepine therapy alone, and additional study is needed to determine whether an interaction exists.
Concomitant administration of an oral antacid increases the oral bioavailability of didanosine.
For more Interactions (Complete) data for DIDEOXYINOSINE (16 total), please visit the HSDB record page.

[1]. Analytical profiles of drug substances and excipients. Journals & Books, 1993, 185-227.

[2]. Evaluation of HIV protease and nucleoside reverse transcriptase inhibitors on proliferation, necrosis, apoptosis in intestinal epithelial cells and electrolyte and water transport and epithelial barrier function in mice. BMC Gastroenterol. 2010 Aug 11;10:90.

[3]. Didanosine. Drugs, 1999, 58, 1099-1135.

Therapeutic Uses
Anti-HIV Agents; Antimetabolites; Reverse Transcriptase Inhibitors
Didanosine in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. Additionally, didanosine is indicated in the treatment of adults and children over 6 months of age with advanced HIV infection who are intolerant of zidovudine therapy or who have demonstrated significant clinical or immunologic deterioration during zidovudine therapy; didanosine is also indicated in the treatment of adults with advanced HIV infection who have received prior zidovudine therapy. /Included in US product labeling/
Didanosine is also used in combination with zidovudine. /NOT included in US product labeling/

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Drug Warnings
Patients with renal impairment (ie, creatinine concentrations less than 60 ml/minute) may be at increased risk of adverse effects during didanosine therapy because of decreased clearance or altered metabolism of the drug; a decrease in dosage in recommended in these patients. Each didanosine chewable/dispersible, buffered tablet contains 8.6 mEq of magnesium hydroxide, which may present an excessive magnesium load in patients with clinically important renal impairment, especially during prolonged therapy with the drug; other didanosine dosage forms should be considered for use in these patients.
Pancreatitis has occurred in 3% of children (2 of 60) receiving didanosine in dosages less than 300 mg/sq m daily and in 13% of those (5 of 38) receiving higher dosages. Although neuropathy has been reported only rarely in children receiving didanosine, signs and symptoms of neuropathy may be difficult to assess in children, and physicians should monitor children closely for this adverse effect.
Retinal changes and optic neuritis have been reported in a few children receiving didanosine. The manufacturer recommends that all children receiving the drug receive dilated retinal examinations every 6 months and whenever a change in vision occurs.
Because oral absorption of ciprofloxacin may be decreased in the presence of antacids containing magnesium, calcium, or aluminum, the manufacturer of didanosine recommends that didanosine (given as chewable/dispersible, buffered tablets; buffered powder for oral solution; or unbuffered pediatric powder for oral solution that has been admixed with antacid) be administered at least 2 hours after or 6 hours before an oral dose of ciprofloxacin. In 8 HIV-infected patients, the steady-state AUC of ciprofloxacin was decreased an average of 26% when ciprofloxacin was administered 2 hours prior to a chewable/dispersible, buffered didanosine tablet. The AUC of ciprofloxacin was on average 98% lower in healthy individuals who received ciprofloxacin and didanosine-placebo buffered tablets concomitantly.
For more Drug Warnings (Complete) data for DIDEOXYINOSINE (29 total), please visit the HSDB record page.

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Pharmacodynamics
Didanosine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Didanosine is a hypoxanthine attached to the sugar ring, unlike other nucleoside analogues. Didanosine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. Didanosine is effective against HIV, and usually used in combination with other antiviral therapy. Switching from long term AZT treatment to didanosine has been shown to be beneficial. Didanosine has weak acid stability and therefore, it is often combined with an antacid.

C10H12N4O3

236.23

236.09

69655-05-6

Didanosine-d2

135398739

White to off-white solid powder

1.8±0.1 g/cm3

531.2±60.0 °C at 760 mmHg

193-195 °C

275.0±32.9 °C

0.0±1.5 mmHg at 25°C

1.798

-1.31

2

5

2

17

348

2

C1C[C@@H](O[C@@H]1CO)N2C=NC3=C2N=CNC3=O

BXZVVICBKDXVGW-NKWVEPMBSA-N

InChI=1S/C10H12N4O3/c15-3-6-1-2-7(17-6)14-5-13-8-9(14)11-4-12-10(8)16/h4-7,15H,1-3H2,(H,11,12,16)/t6-,7+/m0/s

9-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-3H-purin-6-one

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)

Solubility in Formulation 1: ≥ 2.08 mg/mL (8.80 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 (8.80 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 (8.80 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.)