Methoxsalen (15 mg/kg, i.p., single dosage) raises the Cmax and AUC of nicotine while prolonging its half-life (by four times) and decreasing its clearance (by six times) [1].

Animal/Disease Models: Male adult ICR mice [1]
Doses: 15 mg/kg
Route of Administration: intraperitoneal (ip) injection, single dose
Experimental Results: nicotine plasma concentration is still higher than 10ng/ml at 6 hrs (hrs (hours)). The analgesic and cooling effects of induced nicotine lasted for nearly 6 hrs (hrs (hours)) and 24 hrs (hrs (hours)).

Absorption, Distribution and Excretion
In both mice and man, methoxsalen is rapidly metabolized. Approximately 95% of the drug is excreted as a series of metabolites in the urine within 24 hours (Pathak et al. 1977).
After oral admin of (3)H 8-methoxypsoralen to rats, it was absorbed rapidly and max blood level was observed at 10 min. Moderate radioactivity was found in liver and kidneys at 0.5-4 hr, and low levels in other tissues. ... 62.8% of radioactivity was excreted in urine and 20.4% in feces within 24 hr and 65.1% and 21.9% during 6 days, respectively. In bile, 30.0% was also recovered within 24 hr; this passed through enterohepatic circulation.
Improvement in effective bioavailability of methoxsalen was achieved when it was administered to rats and dogs in solution as compared to suspension. Much earlier and higher peak levels were observed for the solution in both animals.
Max serum concentration /in patients/ occurred between 0.5 and 2 hr after oral administration of 0.6 mg/kg methoxsalen. There was significant negative correlation between logarithm of serum concentration and minimum phototoxic dose. Hence degree of photosensitivity appears to be related to serum level of methoxsalen.
Single iv doses of 5 mg/kg body weight (14)C methoxsalen to dogs disappeared rapidly from plasma, although small levels of radioactivity persisted for 5 weeks after administration. Evidence suggested that the persistent plasma radioactivity was due to a metabolite bound to plasma protein. Elimination occurred in both urine and bile; 45% of the dose appeared in the urine and 40% in the feces within 72 hrs of administration.
For more Absorption, Distribution and Excretion (Complete) data for 8-Methoxypsoralen (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
After oral administration of 8-methoxypsoralen to rats, metabolites in urine were; 8-hydroxypsoralen, 5-hydroxy-8-methoxypsoralen, 5,8-dioxopsoralen, 5,8-dihydroxypsoralen, 4,6,7-trihydroxy-5-coumaranoyl-beta-acrylic acid, 4,6-dihydroxy-7-methoxy-5-coumaranoyl-beta-acrylic acid.
Although the exact metabolic fate of methoxsalen has not been fully established, the drug is rapidly and apparently almost completely metabolized. Methoxsalen is demethylated to 8-hydroxypsoralen (8-HOP), and methoxsalen and 8-HOP are conjugated with glucuronic acid and sulfate; other unidentified metabolites have also been detected. Methoxsalen and 8-hydroxypsoralen and their conjugates are excreted in urine. Following oral administration of methoxsalen, 80-90% of the drug is excreted in urine within 8 hours as hydroxylated, glucuronide, and sulfate metabolites; less than 0.1% of a dose is excreted in urine as unchanged drug. About 95% of the drug is excreted in urine within 24 hours as metabolites.
Methoxsalen is extensively metabolized, and less than 2% of the drug is excreted unchanged in the urine. Four urinary metabolites were isolated; 3 of them resulted from opening of the furan ring: these are 7-hydroxy-8-methoxy-2-oxo-2H-1-benzopyran-6-acetic acid, alpha,7-dihydroxy-8-methoxy-2-oxo-2H-1-benzopyran-6-acetic acid, and an unknown conjugate of the former at the 7-hydroxy position. The fourth metabolite, formed by opening of the pyrone ring, is an unknown conjugate of (Z)-3-(6-hydroxy-7-methoxybenzofuran-5-yl)-2-propenoic acid.
Methoxsalen has known human metabolites that include 9-Methoxy-5,7,11-trioxatetracyclo[8.4.0.03,8.04,6]tetradeca-1,3(8),9,13-tetraen-12-one.

Route of Elimination: In both mice and man, methoxsalen is rapidly metabolized. Approximately 95% of the drug is excreted as a series of metabolites in the urine within 24 hours (Pathak et al. 1977).
Half Life: Approximately 2 hours

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Biological Half-Life
Approximately 2 hours
The elimination half-life of methoxsalen is reportedly about 0.75-2.4 hours.

Toxicity Summary
IDENTIFICATION AND USE: 8-Methoxypsoralen (8-MOP) belongs to a group of compounds known as psoralens, or furocoumarins. It is used as suntan accelerator and sunburn protector. 8-MOP is used for photochemotherapy (PUVA, 8-MOP with long wave UVA radiation) for psoriasis. It is also used in conjunction with long wavelength UVA or sunlight to repigment vitiliginous skin in patients with idiopathic vitiligo. Oral 8-MOP is used in conjunction with photopheresis for the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma. HUMAN STUDIES: In Indian patients treated for vitiligo, 12 percent developed keratoses, but not cancer. Of 52 patients under continued PUVA treatment,12 subjects had small superficial dermal amyloid deposits. Three of 20 healthy volunteers given increasing doses of topically applied 1% 8-MOP 3 times a week plus UV light developed photoallergy. Other adverse dermatologic effects associated with PUVA therapy include skin freckling, hypopigmentation, uneven or excessive tanning, dry skin, vesiculation and bullae formation, generalized exfoliation, nonspecific rash, urticaria, miliaria, folliculitis, acneiform eruption, aggravation or extension of psoriasis, hyperpigmentation of psoriatic lesions, cutaneous tenderness, severe skin pain, onycholysis, pigmentation of the nails, and exacerbation of latent photosensitive dermatoses. Kaposi's varicelliform eruption was reported after the initiation of PUVA therapy. Phototoxic reactions including severe edema and erythema, and painful blistering, burning, and peeling of skin may occur with methoxsalen and conventional UV light. In addition, PUVA therapy has produced severe burns requiring hospitalization, and marked hyperpigmentation and aging of skin. Nausea is the most common adverse effect of oral 8-MOP, occurring in about 10% of patients. GI disturbances may also occur with PUVA therapy utilizing 8-MOP. Pruritus occurs in about 10% of patients treated with PUVA therapy utilizing 8-MOP. A case of a bilateral macular toxicity was reported in a male treated with 8-MOP for vitiligo. A 59-year-old white woman developed a toxic hepatitis while on oral 8-MOP PUVA treatment. There are reports of carcinomas in patients treated with 8-MOP. In a cohort study of 1373 patients treated with 8-MOP plus UV light for psoriasis, 30 patients developed 19 basal-cell carcinomas and 29 squamous-cell carcinomas of the skin. There is increased risk for melanoma in PUVA patients. Some patients developing melanoma did so even after having ceased PUVA therapy over 5 years earlier. Treatment with 8-MOP plus UV irradiation resulted in significant increase of chromosomal aberrations in lymphocyte chromosomes of 1/8 patients, slight but non-significant increases in 6 and no increase in one patient, sister chromatid exchanges were also observed. No chromosome aberrations or sister chromatid exchanges were observed in psoriasis patients treated with the combination but when white blood cells removed from patients after treatment were irradiated with UV light in vitro, there was a significant increase in sister chromatid exchanges. More point mutations, as indicated by the increased incidence of 6-thioguanine-resistant lymphocytes, were observed in patients treated with psoralen drugs and UV irradiation than in healthy controls. ANIMAL STUDIES: Severe reactions were reported in guinea pigs given 40 mg of 8-MOP by i.p. injection one hour before they were exposed to long wavelength UV continuously for 24 hours. White guinea pigs developed ulceration of the lids, edema of the corneas, congestion of iris vessels, permanently dilated pupils, and multiple anterior cortical punctate opacities in the lenses. In black guinea pigs the lids and iris were less damaged. Guinea pigs given 8-MOP at 80 to 100 mg/kg showed no damage to the eyes unless they were also exposed to long wavelength UV. Topical or i.p. 8-MOP has been reported to be a potent photocarcinogen in albino mice and hairless mice. However, 8-MOP given by the oral route to albino mice exerted a protective effect against UV carcinogenesis. Mice given 8-MOP in their diet showed 38% ear tumors 180 days after the start of UV therapy compared to 62% for controls. Hairless mice were given daily skin applications of 40 ug of 8-MOP 30-60 minutes before a whole body 10 minute exposure to UV light (300-400 nm) 5 days a week. The number of tumors per mouse was significantly higher in animals given 8-MOP plus UV. Most of the tumors were squamous cell carcinomas; others were fibrosarcomas, lymphosarcomas, sebaceous adenomas and hemangiomas. In mice, ip injection of 4 mg/kg bw 8-MOP followed by exposure to long wave UV irradiation (320-400 nm) resulted in severe toxic effects including erythema, burns and liver damage. In 2 yr gavage studies in male rats using 8-MOP without UV radiation reported increased incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney and carcinomas of the Zymbal gland. Dose related nonneoplastic lesions in male rats included increased severity of nephropathy and mineralization of the kidney and forestomach lesions. There was no evidence of carcinogenic activity of 8-MOP for female rats given the chemical at 37.5 or 75 mg/kg/day for 2 yr. Doses of 80 to 160 mg/kg/day given during organogenesis caused significant fetal toxicity in rats, which was associated with significant maternal weight loss, anorexia and increased relative liver weight. 8-MOP caused an increase in skeletal malformation and variations at doses of 80 mg/kg/day and above. 8-MOP was mutagenic in the Ames test with metabolic activation. In the absence of metabolic activation and UV light, 8-MOP was clastogenic in vitro (sister chromatid exchange and chromosome aberrations in Chinese hamster ovary cells). 8-MOP also caused DNA damage, interstrand cross-links and errors in DNA repair.
Methoxsalen is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen. The mechanism of action many furocoumarins is based on their ability to form photoadducts with DNA and other cellular components such as RNA, proteins, and several proteins found in the membrane such as phospholipases A2 and C, Ca-dependent and cAMPdependent protein-kinase and epidermal growth factor. Furocoumarins intercalate between base pairs of DNA and after ultraviolet-A irradiation, giving cycloadducts. (L579).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of methoxsalen during breastfeeding. Expert opinion indicates that due to the photosensitizing effects of methoxsalen, breastfeeding should be withheld for 24 hours after an oral dose to allow for 95% of the drug to be eliminated in the mother's urine. The same precaution probably applies to patients receiving methoxsalen as a part of therapy for cutaneous T-cell lymphoma. Use of topical methoxsalen is not contraindicated during breastfeeding, but avoid direct contact of the treated skin with the skin of the infant.
◉ 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.

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Interactions
Upon exposure to UVA light, psoralens can induce DNA interstrand cross-links (ICLs), which can block DNA replication and transcription. Among the psoralen derivatives, 8-methoxypsoralen (8-MOP) is conventionally applied for psoriasis therapy, and amotosalen S59 is used to inactivate bacterial and viral pathogens in blood components. In addition to the ICL formation, psoralens also readily form various monoadducts (MAs) with thymidine residues in DNA when exposed to UVA light, and the biological implications for these monoadducts remain unclear. Here, we reported a method that encompassed digestion with a single enzyme (nuclease P1) and LC-MS/MS, for the simultaneous quantification of ICL and MAs induced in human cells exposed with 8-MOP or S59 and UVA light. Our results showed that the yield of ICL induced by S59, which increased from 3.9 to 12.8 lesions/10(3) nucleotides as the dose of UVA light increased from 0.5 to 10.0 J/sq cm, was approximately 100 fold more than that induced by 8-MOP. In addition, three and five products were identified as 8-MOP- and S59-MAs, respectively, and the yields of MAs were significantly lower than that for ICL. The yields of the three 8-MOP-MAs were 7.6-2.2, 1.9-9.9, and 7.2-51 per 10(6) nucleotides and those of the five S59-MAs were 215-19, 106-39, 25-21, 32-146, and 22-26 per 10(6) nucleotides as the dose of UVA light increased from 0.5 to 10.0 J/sq cm. Although the yields of MAs induced by 8-MOP and S59 were lower than those of the respective ICLs under the same exposure conditions, the formation of appreciable amounts of MAs might account for some of the mutations induced by psoralens.
/The authors/ reported recently that the drug methoxsalen, a potent suicide inhibitor of hepatic cytochrome P-450, decreases the metabolic activation of acetaminophen and prevents its hepatotoxicity in mice. /Investigators/ have now studied the effects of methoxsalen on the metabolism of acetaminophen in humans. In vitro, 100 uM methoxsalen decreased by 40% the covalent binding of a (3)H-acetaminophen metabolite to microsomal proteins after incubation of (3)H-acetaminophen with human liver microsomes and an NADPH-generating system. In vivo, a single oral dose of methoxsalen (30 mg), given 3 hr before acetaminophen (1 g), decreased by 38% the partial apparent oral salivary clearance of acetaminophen into glutathione-derived conjugates (the end products of its oxidative metabolism) in nine human volunteers. These observations demonstrate that methoxsalen decreases the metabolic activation of acetaminophen in humans.
To determine the effect of methoxsalen on coumarin 7-hydroxylation in humans in vivo, five subjects were given 45 mg of methoxsalen and 5 mg of coumarin. Methoxsalen inhibited in vivo coumarin metabolism by 47 +/- 9.2% (mean +/- SEM). Methoxsalen was metabolized in human liver microsomes at the rate of 50-100 pmol/mg protein/min (approx. 30% of the activity in mouse liver microsomes). Metabolism was not inhibited by the anti-Cyp2a-5 antibody in human liver microsomes. NIH 3T3 cells stably expressing catalytically active CYP2A6 enzyme did not metabolize methoxsalen, indicating that CYP2A6 does not accept methoxsalen as a substrate. In pyrazole-induced mouse liver microsomes, methoxsalen metabolism was inhibited by the anti-Cyp2a-5 antibody. Cyp2a-5 protein expressed in the yeast Saccharomyces cerevisiae was capable of metabolizing methoxsalen, indicating that methoxsalen is a substrate of Cyp2a-5. Although kinetic studies indicated that the inhibition of coumarin 7-hydroxylation by methoxsalen is competitive in human liver microsomes, methoxsalen does not appear to be a substrate for CYP2A6. Methoxsalen and coumarin have the potential /for/ strong metabolic interactions in man.
Furanocoumarins increase the bioavailability of drugs that are CYP3A4 substrates. A possible interaction of methoxsalen with cyclosporine was evaluated in 12 healthy volunteers following oral administration of 40 mg methoxsalen, 200 mg cyclosporine, or a combination of both in a randomized crossover study. Methoxsalen increased area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of cyclosporine by 29% (range, -20% to 172%; P < .05) and 8% (range, -10% to 26%; P < .05), respectively, compared to cyclosporine alone. The AUC geometric means ratio (95% confidence interval) for cyclosporine plus methoxsalen/cyclosporine alone was 1.14 (1.02, 1.27), and treatments were therefore not bioequivalent. Methoxsalen causes a clinically significant interaction with cyclosporine in some susceptible individuals. The reasons for susceptibility and the clinical implications for chronic cyclosporine administration have not been established. Caution is recommended in combination therapy, and more frequent monitoring of cyclosporine plasma levels and clinical monitoring is advised.
For more Interactions (Complete) data for 8-Methoxypsoralen (25 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse sc 860 mg/kg
LD50 Mouse ip 310 mg/kg
LD50 Mouse oral 423 mg/kg
LD50 Rat ip 158 mg/kg
LD50 Rat oral 791 mg/kg

[1]. Pharmacokinetic and Pharmacodynamics Studies of Nicotine After Oral Administration in Mice: Effects of Methoxsalen, a CYP2A5/6 Inhibitor. Nicotine Tob Res. 2014 Jan;16(1):18-25.

Therapeutic Uses
Cross-Linking Reagents; Photosensitizing Agents
Photochemotherapy (methoxsalen with long wave UVA radiation) is indicated for the symptomatic control of severe, recalcitrant, disabling psoriasis not adequately responsive to other forms of therapy and when the diagnosis has been supported by biopsy. Photochemotherapy is intended to be administered only in conjunction with a schedule of controlled doses of long wave ultraviolet radiation. /Included in US product label/
Methoxsalen is used orally (as conventional capsules) or topically in conjunction with controlled exposure to long wavelength ultraviolet radiation (UVA) or sunlight to repigment vitiliginous skin in patients with idiopathic vitiligo. The liquid-filled capsules currently are not approved by the US Food and Drug Administration for this use. Clinical response to methoxsalen is erratic and unpredictable and is cosmetically acceptable in only a small percentage of patients with vitiligo. Complete cures following psoralen therapy are infrequent; only about one-third of patients with vitiligo have an appreciable amount of pigmentation restored. In one study of 20 patients treated with topical methoxsalen and blacklight, complete repigmentation occurred in only 3 patients. In one study using UVA light and oral methoxsalen or oral trioxsalen for 12-14 months, 73% of vitiligo patients had some pigmentation restored and, in 23% of patients, pigmentation improved by about 73%. Repigmentation varies among patients in completeness, time of onset, and duration. Methoxsalen-induced repigmentation occurs more rapidly on fleshy areas such as the face, abdomen, and buttocks than on bony areas such as the dorsa of the hands and feet. To retain new pigment, periodic treatment with the drug and some form of UVA light is often required; however, in one study, 90% or more of the new pigment established during oral methoxsalen and conventional UV light therapy remained in 85% of patients 8-14 years after methoxsalen treatment was discontinued.
Oral methoxsalen is used in conjunction with photopheresis with the UVAR instrument for the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL; e.g., mycosis fungoides, Sezary syndrome). Limited evidence indicates that photopheresis therapy (e.g., administered once daily for 2 consecutive days per month) can produce reductions in the size and/or severity of skin lesions without serious toxicity; sustained responses (2 years or longer) have occurred in some patients. For detailed information on the use of oral methoxsalen in conjunction with photopheresis in patients with cutaneous T-cell lymphoma, clinicians should consult the manufacturer's labeling for methoxsalen and the UVAR instrument and other specialized references and published protocols.
For more Therapeutic Uses (Complete) data for 8-Methoxypsoralen (6 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ Methoxsalen with UV radiation should be used only by physicians who have special competence in the diagnosis and treatment of psoriasis and who have special training and experience in photochemotherapy. The use of Psoralen and ultraviolent radiation therapy should be under constant supervision of such a physician. For the treatment of patients with psoriasis, photochemotherapy should be restricted to patients with severe, recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, and only when the diagnosis is certain. Because of the possibilities of ocular damage, aging of the skin, and skin cancer (including melanoma), the patient should be fully informed by the physician of the risks inherent in this therapy.
/BOXED WARNING/ Methoxsalen Capsules, USP (Soft Gelatin Capsules) should not be used interchangeably with regular methoxsalen capsules or methoxsalen hard gelatin capsules. This new dosage form of methoxsalen exhibits significantly greater bioavailability and earlier photosensitization onset time than previous methoxsalen dosage forms. Patient should be treated in accordance with the dosimetry specifically recommended for this product. The minimum phototoxic dose (MPD) and phototoxic peak time after drug administration prior to onset of photochemotherapy with this dosage form should be determined.
/Methoxsalen is contraindicated in:/ patients exhibiting idiosyncratic reactions to psoralen compounds; patients possessing a specific history of light sensitive disease states should not initiate methoxsalen therapy. Diseases associated with photosensitivity include lupus erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma pigmentosum, and albinism; patients exhibiting melanoma or possessing a history of melanoma; patients exhibiting invasive squamous cell carcinomas; patients with aphakia, because of the significantly increased risk of retinal damage due to the absence of lenses.
Phototoxic reactions including severe edema and erythema, and painful blistering, burning, and peeling of skin may occur with methoxsalen and conventional UV light. In addition, PUVA therapy has produced severe burns requiring hospitalization, and marked hyperpigmentation and aging of skin. When peeling or blistering occurs, the skin becomes more sensitive to UV light. Phototoxic reactions to methoxsalen occur most commonly when the skin is overexposed to UV light or when dosage is excessive. Severe burns may occur if treated skin is accidentally exposed to additional UV light. Some reports indicate that the incidence of psoralen-induced phototoxicity may be slightly reduced by concurrent application of benzophenone sunscreens.
For more Drug Warnings (Complete) data for 8-Methoxypsoralen (27 total), please visit the HSDB record page.

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Pharmacodynamics
Methoxsalen selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of Methoxsalen-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.

C12H8O4

216.1895

216.042

298-81-7

Methoxsalen-d3;80386-99-8

4114

White to light yellow solid powder

1.4±0.1 g/cm3

414.8±45.0 °C at 760 mmHg

143-148 ºC

204.7±28.7 °C

0.0±1.0 mmHg at 25°C

1.635

1.93

0

4

1

16

325

0

QXKHYNVANLEOEG-UHFFFAOYSA-N

InChI=1S/C12H8O4/c1-14-12-10-8(4-5-15-10)6-7-2-3-9(13)16-11(7)12/h2-6H,1H3

9-methoxyfuro[3,2-g]chromen-7-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)

DMSO : ~50 mg/mL (~231.28 mM)
H2O : ~0.67 mg/mL (~3.10 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.56 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 (11.56 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.)