The pharmacokinetic behavior of the soy isoflavone metabolite S-(-)equol and its diastereoisomer R-(+)equol in healthy adults determined by using stable-isotope-labeled tracers

Abstract

Background: The nonsteroidal estrogen equol occurs as diastereoisomers, S-(-)equol and R-(+)equol, both of which have significant biological actions. S-(-)equol, the naturally occurring enantiomer produced by 20-30% of adults consuming soy foods, has selective affinity for estrogen receptor-beta, whereas both enantiomers modulate androgen action. Little is known about the pharmacokinetics of the diastereoisomers, despite current interest in developing equol as a nutraceutical or pharmaceutical agent.

Objective: The objective was to compare the pharmacokinetics of S-(-)equol and R-(+)equol by using [13C] stable-isotope-labeled tracers to facilitate the optimization of clinical studies aimed at evaluating the potential of these diastereoisomers in the prevention and treatment of estrogen- and androgen-dependent conditions.

Design: A randomized, crossover, open-label study in 12 healthy adults (6 men and 6 women) compared the plasma and urinary pharmacokinetics of orally administered enantiomeric pure forms of S-(-)[2-13C]equol, R-(+)[2-13C]equol, and the racemic mixture. Plasma and urinary [13C]R-equol and [13C]S-equol concentrations were measured by tandem mass spectrometry.

Results: Plasma [13C]equol concentration appearance and disappearance curves showed that both enantiomers were rapidly absorbed, attained high circulating concentrations, and had a similar terminal elimination half-life of 7-8 h. The systemic bioavailability and fractional absorption of R-(+)[2-13C]equol were higher than those of S-(-)[2-13C]equol or the racemate. The pharmacokinetics of racemic (+/-)[2-13C]equol were different from those of the individual enantiomers: slower absorption, lower peak plasma concentrations, and lower systemic bioavailability.

Conclusions: The high bioavailability of both diastereoisomers contrasts with previous findings for the soy isoflavones daidzein and genistein, both of which have relatively poor bioavailability, and suggests that low doses of equol taken twice daily may be sufficient to achieve biological effects.

FIGURE 1

Typical chiral phase liquid chromatography tandem mass spectrometry profiles of the negative ion multiple reaction ion monitoring (MRM) transition m/z 242→121 for plasma samples collected 2 h after administration of 20 mg S-(−)[2-¹³C]equol, R-(+)[2-¹³C]equol, and (±)[2-¹³C]equol to the same healthy adult. Shown for comparison is a sample of plasma taken at baseline and the same sample after adding the enantiomeric pure standards of S-(−)[2-¹³C]equol and R-(+)[2-¹³C]equol. These analyses established a lack of biotransformation of the individual enantiomers after oral administration.

FIGURE 2

Typical plasma equol concentration appearance and disappearance curves obtained in a healthy adult after administration of a single-bolus, 20-mg dose of S-(−)[2-¹³C]equol, R-(+)[2-¹³C]equol, and (±)[2-¹³C]equol.

FIGURE 3

Log linear plots of appearance and disappearance curves for mean (±SD) plasma S-(−)[2-¹³C]equol and R-(+)[2-¹³C]equol concentrations obtained in the same 12 healthy adults after administration of a single-bolus, 20-mg dose of S-(−)[2-¹³C]equol and R-(+)[2-¹³C]equol administered in a randomized crossover design study; data for (±)[2-¹³C]equol are not included so that the comparison of the characteristics of the 2 enantiomers is clear. C_max, maximum plasma concentration.

FIGURE 4

Cumulative urinary excretion of S-(−)[2-¹³C]equol, R-(+)[2-¹³C]equol, and (±)[2-¹³C]equol over 72 h in 12 healthy adults after administration of a single-bolus, 20-mg dose of S-(−)[2-¹³C]equol, R-(+)[2-¹³C]equol, and (±)[2-¹³C]equol.

FIGURE 5

Mean (±SD) urinary excretion of S-(−)[2-¹³C]equol, R-(+)[2-¹³C]equol, and (±)[2-¹³C]equol in 12-h pooled collections over 72 h in 12 healthy adults after administration of a single-bolus, 20-mg dose of S-(−)[2-¹³C]equol, R-(+)[2-¹³C]equol, and (±)[2-¹³C]equol.

FIGURE 6

Mean (±SD) total recovery of S-(−)[2-¹³C]equol [S-(−)], R-(+)[2-¹³C]equol [R-(+)], and (±)[2-¹³C]equol (±) over 72 h in 12 healthy adults after administration of a single-bolus, 20-mg dose of S-(−)[2-¹³C]equol, R-(+)[2-¹³C]equol, and (±)[2-¹³C]equol. Urinary recovery of R-(+)[2-¹³C]equol was higher than that of either S-(−)[2-¹³C]equol or (±)[2-¹³C], but the differences were not statistically significant when calculated by repeated-measures ANOVA.