Furafylline, as a long-acting replacement for theophylline in the treatment of asthma, is a methylxanthine derivative[1].
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].
参考文献:
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.
| 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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参考文献: 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. | |
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