Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in man.

Abstract

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 0-deethylase activity of microsomal fractions of human liver, a reaction catalysed by P450IA2, with an IC50 value of 0.07 FLM.3 Furafylline had either very little or no effect on human monooxygenase activities catalysed by other isoenzymes of P450, including P4501ID1, P4501IC, P450IIIA. Of particular interest, furafylline did not inhibit P4501A1, 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 Ni-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 P450IA2 in vivo in man. 6 Although furafylline selectively inhibited P450IA2, relative to P4501A1, 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.

Oxidation of the Flavonoids Galangin and Kaempferide by Human Liver Microsomes and CYP1A1, CYP1A2, and CYP2C9

“…To determine the potential contribution of other P450 isoforms to the hepatic metabolism of galangin and kaempferide, we used the CYP1A2-specific inhibitor furafylline in further experiments with the pooled human liver microsomes. This mechanism-based inhibitor (Sesardic et al, 1990;Clarke et al, 1994;Clement and Demesmaeker, 1997), at a …”

“…Furafylline (20 M), a selective CYP1A2 inhibitor (Sesardic et al, 1990;Clarke et al, 1994;Clement and Demesmaeker, 1997) was preincubated for 15 min with the enzyme mixture before the addition of substrate. Sulfaphenazole (25 M), a selective inhibitor of CYP2C9 (Eagling et al, 1998;Giancarlo et al, 2001), was added together with the substrates.…”

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

“…The levels used in both studies are greater than those achievable after current therapeutic doses of paracetamol. However, it may be possible to increase paracetamol doses in patients by combining treatment with furafylline, a potent CYP1A2 inhibitor (Sesardic et al, 1990). Plasma steady-state levels of furafylline can reach 5.8 mM in humans (Tarrus et al, 1987), and the IC 50 for purified CYP1A2 is 0.07 mM (Sesardic et al, 1990), indicating that the use of furafylline to inhibit paracetamol activation in the liver is feasible.…”

Theophylline has no advantages over caffeine as a putative model drug for assessing CYP1A2 activity in humans

“…this study could be explained by a number of factors, such as the small number of subjects studied (n=12), and by the relatively low variability in CYP1A2 activity within this References sample. Thus, it can be estimated that a sample size of 12 volunteers gives the study a power of only 48%, when a [27,36]. Thus, it is possible that the poor correlation clearances.…”