Pharmacokinetics and Ex Vivo Activity of 7-Methylxanthine, an Inhibitor of Monosodium Urate Crystallization

Abstract

Background/Objectives: 7-Methylxanthine (7-MX) is a naturally occurring metabolite of caffeine and theobromine that can inhibit the crystallization of monosodium urate (MSU) and may be useful for the prevention or treatment of gout. However, the pharmacokinetics and ex vivo activity of 7-MX remain poorly characterized. Methods: The present study assessed the pharmacokinetics of 7-MX in Sprague Dawley rats following a single oral dose (30 mg/kg), and the ex vivo inhibition of MSU crystallization by 7-MX in rat plasma after the repeated administration of oral 7-MX. Results: The pharmacokinetic analysis showed that 7-MX reached peak plasma concentration (C_max ≈ 30 µM) at 30 min after administration (t_max), the terminal half-life was approximately 1.4 h, and there was no evidence of accumulation after repeated daily dosing. After repeated administration, the relationship between dose (30 or 60 mg/kg) and plasma concentration was proportional. In vitro and ex vivo crystallization assays demonstrated that 7-MX inhibited MSU crystallization in a concentration-dependent manner. The in vitro studies showed that 100 µM 7-MX inhibited up to 74% of MSU crystallization under supersaturated conditions (400 mg/L urate). The ex vivo experiments indicated that plasma from rats that received 30 or 60 mg/kg of 7-MX had 41.4% and 52.6% inhibition of crystallization, consistent with the measured plasma concentrations. Conclusions: These findings confirm that oral administration of 7-MX to rats led to a plasma level that was sufficient to decrease MSU crystallization in plasma, and there were no observable toxicities. These results support the potential of 7-MX as a safe oral treatment for gout, especially in combination with urate-lowering therapies, such as allopurinol. Further clinical investigations are warranted to confirm the therapeutic potential of 7-MX in humans.

Keywords: 7-methylxanthine; gout; monosodium urate; oral administration; pharmacokinetics.

Figure 1

Plasma concentration of 7-MX in male and female Sprague Dawley rats after single oral dose (30 mg/kg). Concentrations were quantified in plasma samples from 6 males and 6 females. Results are expressed as mean ± SD (N = 3 per sex and time point).

Figure 2

Effect of 7-MX concentration in rat plasma on amount of MSU crystallization when initial urate concentration was 300 mg/L (A) and 400 mg/L (B), and percent inhibition of MSU crystallization by different concentrations of 7-MX for urate concentrations of 300 and 400 mg/L (C). Results in (A,B) are means ± SDs (N = 2). Curves in (C) were from fits to nonlinear regression model with four parameters.

Figure 3

Effect of oral administration of 7-MX (0, 30, or 60 mg/kg) to Sprague Dawley rats on ex vivo inhibition of MSU crystallization in plasma after addition of 300 mg/L (A) and 400 mg/L urate (B), and percent inhibition of crystallization by different concentrations of 7-MX for urate concentrations of 300 and 400 mg/L (C). Results in (A,B) are means ± SDs (N = 6). * p < 0.05; ** p < 0.01. In (C), abscissa indicates plasma levels of 7-MX in rats that received 0, 30, or 60 mg/L 7-MX, and lines are from Pearson’s correlation. Dashed line represents an inhibition of 0%.