Furafylline
(Synonyms: 呋拉茶碱) 目录号 : GC32855
Furafylline, as a long-acting replacement for theophylline in the treatment of asthma, is a methylxanthine derivative[1].
Cas No.:80288-49-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
human hepatocytes |
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Preparation Method |
25 µM; for 2.2 h at 37 °C |
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Reaction Conditions |
Sunitinib (10 µM) was incubated with cryopreserved CYP3A5-genotyped human hepatocytes (0.5 × 106 cells/mL in KHB) from 12 individual donors in suspension for 2.2 h at 37 °C. For each donor, incubations were conducted in at least triplicate (three wells per condition). To examine the effect of P450 1A2 inhibitor furafylline (25 µM) on metabolite formation, hepatocytes were coincubated with sunitinib and furafylline in replicates of 2-4 wells per donor, except for donor ZUJ. |
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Applications |
Furafylline reduced M3 (defluorosunitinib) and M5 (glutathione conjugate) formation by 73.2% ± 0.89% and 81.4% ± 4.84%, respectively, compared to the control. Furafylline reduced M1 (N-desethylsunitinib) formation by only 19.4% ± 5.10% . |
| Animal experiment [2]: | |
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Animal models |
rats |
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Preparation Method |
10 mg/kg; p.o. |
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Dosage form |
Rats were treated 10 mg/kg furafylline orally and test plasma levels of caffeine. |
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Applications |
Plasma levels of caffeine are increased more than 400% in rats given furafylline (10 mg kg-1 p.o.) and caffeine (25 mg kg-1 p.o.) as compared to rats given caffeine alone. |
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References: Burnham EA, et al. Interindividual Variability in Cytochrome P450 3A and 1A Activity Influences Sunitinib Metabolism and Bioactivation. Chem Res Toxicol. 2022 May 16;35(5):792-806. | |
Furafylline, as a long-acting replacement for theophylline in the treatment of asthma, is a methylxanthine derivative[1].
In vitro efficacy test it shown that Furafylline was a potent, non-competitive inhibitor of high affinity phenacetin O-deethylase activity of microsomal fractions of human liver, a reaction catalysed by P450IA2, with an IC50 value of 0.07 µM[1]. In vitro, prior to the initiation of the reaction by the addition of substrate, preincubating microsomes with 10 µM furafylline for 10 min in the presence of NADPH, resulted in marked inhibition of 1A2 activity[2]. In vitro, furafylline has inhibition agaisnt NCMN-O-dealkylation in cynomolgus monkey liver microsomes (CyLM), beagle dog liver microsomes (DLM), minipig liver microsomes (PLM), mouse liver microsomes (MLM) and rat liver microsomes (RLM) with IC50 of 56.36 µM, 26.77 µM, 14.61 µM, 5.73 µM and 1.98 µM, respectively[3].
In vivo test it demonstrated that humanized-liver mice were treated with furafylline (daily oral doses of 13 mg/kg for 3 days) decreased the mean values of the areas under the plasma concentration versus time curves and the maximum concentrations for o-hydroxyphenylacetic acid[4]. In vivo efficacy test it exhibited that beagle dogs were administrated 0.5 and 10 mg/kg orally observed an elimination half-life 2-10 times longer than that of theophylline in a dose-dependent kinetically[5].
References:
Sesardic D, et al. Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in man. Br J Clin Pharmacol. 1990 Jun;29(6):651-63.
Clarke SE, et al. Characterization of the inhibition of P4501A2 by furafylline. Xenobiotica. 1994 Jun;24(6):517-26.
Dai Z, et al. Interspecies Variation in NCMN-O-Demethylation in Liver Microsomes from Various Species. Molecules. 2019 Jul 30;24(15):2765.
Miura T, et al. Roles of human cytochrome P450 1A2 in coumarin 3,4-epoxidation mediated by untreated hepatocytes and by those metabolically inactivated with furafylline in previously transplanted chimeric mice. J Toxicol Sci. 2021;46(11):525-530.
Segura J, et al. Some pharmacokinetic characteristics of furafylline, a new 1,3,8-trisubstituted xanthine. J Pharm Pharmacol. 1986 Aug;38(8):615-8.
| Cas No. | 80288-49-9 | SDF | |
| 别名 | 呋拉茶碱 | ||
| Canonical SMILES | O=C1N(C2=C(N=C(C)N2)C(N1C)=O)CC3=CC=CO3 | ||
| 分子式 | C12H12N4O3 | 分子量 | 260.25 |
| 溶解度 | DMSO : 12.5 mg/mL (48.03 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.8425 mL | 19.2123 mL | 38.4246 mL |
| 5 mM | 0.7685 mL | 3.8425 mL | 7.6849 mL |
| 10 mM | 0.3842 mL | 1.9212 mL | 3.8425 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in man
Br J Clin Pharmacol 1990 Jun;29(6):651-63.PMID:2378786DOI:10.1111/j.1365-2125.1990.tb03686.x.
1. Furafylline (1,8-dimethyl-3-(2'-furfuryl)methylxanthine) is a methylxanthine derivative that was introduced as a long-acting replacement for theophylline in the treatment of asthma. Administration of Furafylline was associated with an elevation in plasma levels of caffeine, due to inhibition of caffeine oxidation, a reaction catalysed by one or more hydrocarbon-inducible isoenzymes of P450. We have now investigated the selectivity of inhibition of human monooxygenase activities by Furafylline. 2. Furafylline was a potent, non-competitive inhibitor of high affinity phenacetin O-deethylase activity of microsomal fractions of human liver, a reaction catalysed by P450IA2, with an IC50 value of 0.07 microM. 3. Furafylline had either very little or no effect on human monooxygenase activities catalysed by other isoenzymes of P450, including P450IID1, P450IIC, P450IIA. Of particular interest, Furafylline did not inhibit P450IA1, assessed from aryl hydrocarbon hydroxylase activity of placental samples from women who smoked cigarettes. 4. It is concluded that Furafylline is a highly selective inhibitor of P450IA2 in man. 5. Furafylline was a potent inhibitor of the N3-demethylation of caffeine and of a component of the N1- and N7-demethylation. This confirms earlier suggestions that caffeine is a selective substrate of a hydrocarbon-inducible isoenzyme of P450 in man, and identifies this as P450IA2. Thus, caffeine N3-demethylation should provide a good measure of the activity of P450IA in vivo in man. 6. Although Furafylline selectively inhibited P450IA2, relative to P450IA1, in the rat, this was at 1000-times the concentration required to inhibit the human isoenzyme, suggesting a major difference in the active site geometry between the human and the rat orthologues of P50IA2.
Characterization of the inhibition of P4501A2 by Furafylline
Xenobiotica 1994 Jun;24(6):517-26.PMID:7975717DOI:10.3109/00498259409043254.
1. Furafylline inhibition of 1A2-related activity in human liver microsomal systems was characterized. This inhibition was time and NADPH dependent. The kinetic constants were measured in human liver microsomes; a Ki of inactivation of 3 microM with a maximum rate constant of 0.27 min-1 were determined. 2. This inactivation process was retarded by the presence of a 1A2 substrate and after complete inhibition was achieved, 1A2 activity could be restored by the addition of fresh microsomes to the incubation mixture. These results are consistent with Furafylline being a suicide substrate for 1A2. 3. Preincubating microsomes for 10 min with 10 microM Furafylline in the presence of NADPH, prior to the initiation of the reaction by the addition of substrate, caused marked inhibition of 1A2 activity. This protocol was tested for specificity against 10 human P450 activities. The activities associated with 1A1, 2A6, 2B6, 2C9(/8), 2C19, 2D6, 2E1, 3A4(/5) and A were not significantly inhibited. 4. Using these conditions Furafylline can be diagnostic of 1A2 involvement in a P450-dependent oxidative reaction.
Study on the inhibitory effect of Furafylline and troleandomycin in the 7-methoxyresorufin-O-demethylase and nifedipine oxidase activities in hepatic microsomes from four poultry species using high-performance liquid chromatography coupled with fluorescence and ultraviolet detection
J Pharm Biomed Anal 2019 Feb 5;164:148-154.PMID:30390556DOI:10.1016/j.jpba.2018.10.031.
The present study reports the in vitro studies with Furafylline and troleandomycin (TAO) as specific inhibitors of activities 7-methoxyresorufin-O-demethylase (MROD) and nifedipine oxidase, catalyzed by cytochrome P450 1 A2 (CYP1 A2) and 3A4 human enzymes, respectively, in hepatic microsomes of quail, duck, turkey and chicken. The results suggest that in chicken and quail the MROD activity is carried out by orthologs CYP1 A4 and 1 A5, meanwhile in duck and turkey by a CYP1 A5 ortholog. The nifedipine oxidase activity is carried out by orthologs of the CYP3A family in the four bird species. The use of Furafylline and TAO significantly decreased these activities (P < 0.05) and suggested that the biotransformation of resorufin methyl ether (RME) may be related to more than one avian ortholog.
Roles of human cytochrome P450 1A2 in coumarin 3,4-epoxidation mediated by untreated hepatocytes and by those metabolically inactivated with Furafylline in previously transplanted chimeric mice
J Toxicol Sci 2021;46(11):525-530.PMID:34719555DOI:10.2131/jts.46.525.
Coumarin is a naturally occurring component of food products but is of clinical interest for its potential hepatotoxicity in humans. In the current study, the pharmacokinetics of coumarin in humanized-liver mice after oral and intravenous administrations (30 mg/kg) were investigated for its transformations to metabolically active coumarin 3,4-epoxide (as estimated by the levels of o-hydroxyphenylacetic acid) and to excretable 7-hydroxycoumarin. After oral administration, control mice metabolized coumarin to o-hydroxyphenylacetic acid at roughly the same rate as that to 7-hydroxycoumarin (total of unconjugated and conjugated forms). In contrast, the in vivo biotransformation of coumarin to o-hydroxyphenylacetic acid by humanized-liver mice was around two orders of magnitude less than that to conjugated and unconjugated 7-hydroxycoumarin. After intravenous administrations of coumarin, differences were observed in the plasma concentrations of o-hydroxyphenylacetic acid between humanized-liver mice treated with Furafylline (daily oral doses of 13 mg/kg for 3 days) and untreated humanized-liver mice. The mean values of the areas under the plasma concentration versus time curves and the maximum concentrations for o-hydroxyphenylacetic acid were significantly lower in the group treated with Furafylline (45% and 57% of the untreated values, respectively). These results suggested that the metabolic activation of coumarin in humans was mediated mainly by P450 1A2, which was suppressed by Furafylline, and that humanized-liver mice orally treated with Furafylline might constitute an in vivo model for metabolically inactivated P450 1A2 in human hepatocytes transplanted into chimeric mice.
Accumulation of caffeine in healthy volunteers treated with Furafylline
Br J Clin Pharmacol 1987 Jan;23(1):9-18.PMID:3814465DOI:10.1111/j.1365-2125.1987.tb03003.x.
The pharmacokinetics and tolerance of repeated oral doses of Furafylline were investigated in normal volunteers. In accord with predictions from single dose studies, steady state was achieved on the first day following the administration of 90 mg and maintained by subsequent daily doses of 30 mg. When corrected for body weight there were no significant differences in minimum and maximum plateau levels of Furafylline between males (1.2-2.0 micrograms ml-1; mean body weight 67.2 kg) and females (1.6-2.6 micrograms ml-1; mean body weight 54.9 kg). The half-life of elimination was less when the plasma concentration was lower than 600 ng ml-1 than during the stationary phase of treatment. Despite constant plasma levels the repeated administration of Furafylline appeared to be associated with the onset of adverse xanthine-like side effects, a finding which was subsequently traced to the presence of, and possible synergism with, accumulating serum levels of caffeine in those volunteers drinking caffeine containing beverages. Subsequent studies showed that a single dose (90 mg) of Furafylline results in a rapid accumulation of caffeine given orally (100 mg twice daily) and that this is accompanied by an elimination half-life of some 50 h and an abrupt decrease in metabolite levels. The furafylline-induced accumulation of caffeine was not influenced by the smoking habits of the subjects, implying that the metabolite pathway blocked by Furafylline is the demethylation of caffeine in position 3, an implication confirmed by the reduced formation of paraxanthine. This demonstration of an unacceptable level of adverse side effects resulting from a potent inhibiting effect of Furafylline on the metabolism of a normal dietary constituent has obvious implications in the interpretation of drug-induced toxicity.