Delavirdine was 50% cytotoxic in H9 and PBMC cells at doses greater than 100 μM. At 100 μM, delavirdine causes less than 8% reduction in peripheral blood lymphocyte viability, indicating its modest cytotoxicity [1]. With an IC50 value of 0.26 μM, delavirdine inhibits HIV-1 reverse transcriptase (RT) in its wild-type form. It also inhibits RT replaced with Y181C and K103N, with IC50 values of 8.32 uM and 7.7 uM, respectively [1].

Delavirdine (U 90152) mesylate is a small circulating component that is quickly absorbed and digested. It is administered orally as a single dosage at 10 mg/kg, 200 mg/kg, or 250 mg/kg. Its capacity to metabolize to dealkylavirdine is restricted or hindered in CD-1 mice (PK research), and its metabolic kinetics are non-linear [1].

Absorption, Distribution and Excretion
Elimination: Fecal: 44% following multiple doses of 330 mg three times a day in healthy volunteers. Renal: 51%, following multiple doses of 330 mg three times a day in healthy volunteers. Less than 5% of the dose is recovered unchanged in urine.
Delavirdine is distributed predominantly into blood plasma.
Delavirdine is well absorbed, especially at pH less than 2.0.
Delavirdine mesylate is rapidly absorbed following oral administration, and peak plasma concentrations of the drug are attained approximately 1 hour after the dose. Following oral administration of 400 mg of delavirdine mesylate 3 times daily in HIV-infected adults, mean steady-state peak plasma concentrations of the drug are 15.98 ug/ml (range: 0.91-45.66 ug/ml), mean trough plasma concentrations are 6.85 ug/ml (range: 0.05-20.55 ug/ml), and mean AUC is 82.19 ughour/ml.
For more Absorption, Distribution and Excretion (Complete) data for DELAVIRDINE MESYLATE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Delavirdine binds extensively to plasma proteins and primarily is metabolized by CYP3A4. The major metabolic pathway results in N-dealkylation. There is considerable intersubject variability in plasma delavirdine concentrations related to differences in CYP3A activity. The CSF-to-plasma ratio is 0.02.
The metabolism of delavirdine in the mouse was extensive and involved amide bond cleavage, N-desalkylation, hydroxylation at the C-6' position of the pyridine ring, and pyridine ring-cleavage as determined by MS and/or 1H and 13C NMR spectroscopies. N-desalkylation and amide bond cleavage were the primary metabolic pathways at low drug doses and, as the biotransformation of delavirdine to desalkyl delavirdine reached saturation or inhibition, amide bond cleavage became the predominant pathway at higher doses and after multiple doses.

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Biological Half-Life
The apparent plasma half-life of delavirdine increases with dose. The mean plasma half-life of delavirdine is 5.8 hours (range: 2-11 hours) in adults receiving a dosage of 400 mg 3 times daily.
Elimination from plasma: Mean, 5.8 hours (range, 2 to 11 hours) following treatment with 400 mg three times a day. The apparent half-life increases with dose.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Delavirdine is no longer marketed in the United States. No published information is available on the use of delavirdine during breastfeeding. Delavirdine is not recommended during breastfeeding. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother. 1993 May;37(5):1127-31.

[2]. Metabolism of the HIV-1 Reverse Transcriptase Inhibitor Delavirdine In Mice. Research Article.

Delavirdine mesylate is the monomethanesulfonic acid salt of delavirdine, a non-nucleoside reverse transcriptase inhibitor with activity specific for HIV-1. Viral resistance emerges rapidly when delavirdine is used alone, so it is therefore used (as the methanesulfonic acid salt) with other antiretrovirals for combination therapy of HIV infection. It has a role as an antiviral drug and a HIV-1 reverse transcriptase inhibitor. It contains a delavirdine.
Delavirdine Mesylate is a mesylate salt form of delavirdine, a synthetic, non-nucleoside reverse transcriptase inhibitor. In combination with other anti-retroviral drugs, this agent has been shown to reduce HIV viral load and increase CD4 leukocyte counts in patients. As an inhibitor of the cytochrome P450 system, delavirdine may result in increased serum levels of co-administered protease inhibitors metabolized by the cytochrome P450 system.
A potent, non-nucleoside reverse transcriptase inhibitor with activity specific for HIV-1.

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Mechanism of Action
After entering the cell, delavirdine binds to a hydrophobic pocket in the p66 subunit of reverse transcriptase. This causes a conformational change to a stable, inactive form of the enzyme. The delavirdine-reverse transcriptase complex is stabilized by hydrogen bonds at residue Lys-103 and strong hydrophobic interactions with residue Pro-236. Much higher concentrations of delavirdine are required to inhibit cellular polymerase than reverse transcriptase.
While the complete mechanism of antiviral activity of delavirdine has not been fully elucidated, the drug inhibits replication of human immunodeficiency virus type 1 (HIV-1) by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase. HIV reverse transcriptase is essential for viral replication, and its activities occur in the host cell cytoplasm after the viral particle penetrates the cell membrane and releases the viral core, but before nuclear entry and chromosomal integration of proviral DNA. The enzyme is multifunctional, with 3 principal activities (ie., RNA-directed DNA polymerase, RNase H, and DNA-directed DNA polymerase functions). Using viral RNA as a template, reverse transcriptase forms a minus strand of viral DNA, creating a double-stranded RNA:DNA hybrid (i.e., RNA-directed DNA polymerase function). The RNase H function of reverse transcriptase facilitates copying of viral RNA by degrading the RNA component of the RNA:DNA hybrid after the RNA is copied, leaving a single minus strand of viral DNA. Using the newly formed minus strand of viral DNA as a template, reverse transcriptase forms the plus strand of viral DNA, converting single-stranded viral DNA to the double-stranded proviral DNA form (i.e, DNA-directed DNA polymerase function). BHAP derivatives, including delavirdine, inhibit the polymerase functions, but not the RNase H function, of reverse transcriptase. The drugs bind directly to heterodimeric HIV-1 reverse transcriptase and exert a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase inhibitor.
Nonnucleoside reverse transcriptase inhibitors affect reverse transcriptase at a different site than nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), and the drugs have different mechanisms of action. Unlike currently available nonnucleoside reverse transcriptase inhibitors, dideoxynucleoside antiretroviral agents require intracellular conversion to triphosphate metabolites, which then compete with naturally occurring deoxynucleoside triphosphates for incorporation into viral DNA by reverse transcriptase and cause premature viral DNA chain termination by preventing further 5 to 3 phosphodiester linkages.

C22H28N6O3S.CH4O3S

552.66678

552.182

147221-93-0

Delavirdine;136817-59-9

441386

White to yellow solid powder

732ºC at 760mmHg

118-120ºC

396.5ºC

2.74E-21mmHg at 25°C

4.531

4

10

6

37

842

0

MEPNHSOMXMALDZ-UHFFFAOYSA-N

InChI=1S/C22H28N6O3S.CH4O3S/c1-15(2)24-19-5-4-8-23-21(19)27-9-11-28(12-10-27)22(29)20-14-16-13-17(26-32(3,30)31)6-7-18(16)25-20;1-5(2,3)4/h4-8,13-15,24-26H,9-12H2,1-3H3;1H3,(H,2,3,4)

methanesulfonic acid;N-[2-[4-[3-(propan-2-ylamino)pyridin-2-yl]piperazine-1-carbonyl]-1H-indol-5-yl]methanesulfonamide

Rescriptor; BHAP-U 90152; U-90152; BHAP U 90152; U90152; BHAP-U-90152; U 90152; DLV

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ≥ 40.3 mg/mL (~72.92 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.52 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 25.0 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: ≥ 2.5 mg/mL (4.52 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 25.0 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: ≥ 2.5 mg/mL (4.52 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 25.0 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.)