Furafylline

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.