Disposition kinetics and effects of menthol.

Clinical pharmacology and therapeutics (1999-08-25)
A Gelal, P Jacob, L Yu, N L Benowitz

Menthol is widely used in a variety of commercial products and foods, but its clinical pharmacology is not well studied. To determine the disposition kinetics and to examine subjective and cardiovascular effects of menthol, we conducted a crossover placebo-controlled study that compared pure menthol versus placebo, along with an uncontrolled exposure to menthol in food or beverage. A novel assay for the measurement of menthol in biological fluids was also developed. Twelve subjects were studied; each received a 100 mg l-menthol capsule, a placebo capsule, and 10 mg menthol in mint candy or mint tea on three different occasions. Plasma and urine levels of menthol and conjugated menthol (glucuronide), cardiovascular measurements, and subjective effects were measured at frequent intervals. Menthol was rapidly metabolized, and only menthol glucuronide could be measured in plasma or urine. The plasma half-life of menthol glucuronide averaged 56.2 minutes (95% confidence interval [CI], 51.0 to 61.5) and 42.6 minutes (95% CI, 32.5 to 52.7) in menthol capsule and mint candy/mint tea conditions, respectively (P < .05). The plasma area under the plasma concentration-time curve ratios for menthol capsule to mint candy/mint tea treatment averaged 9.2 (95% CI, 8.2 to 10.1). Urinary recovery of menthol as the glucuronide averaged 45.6 and 56.6% for menthol capsule and mint candy/tea, respectively (difference not significant). After menthol capsule dosing, the decrease in heart rate was less than the decrease after placebo administration (P < .05). Menthol reduced subjective vigor value at 30 minutes. We conclude that pure menthol and menthol in food or beverages have a similar systemic bioavailability and that menthol has a small cardioaccelerating effect.

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L-Menthol, Pharmaceutical Secondary Standard; Certified Reference Material
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