Pharmacokinetics behaviors of l-menthol after inhalation and intravenous injection in rats and its inhibition effects on CYP450 enzymes in rat liver microsomes

Abstract

1. l-Menthol, as a kind of monocyclic terpene, is widely used in inhalation formulations, food and tobacco. The purpose of this study was to investigate the pharmacokinetic behavior of l-menthol as well as its influence on the activities of cytochrome P450 enzymes.

2. The pharmacokinetic behaviors of l-menthol after inhalation (50 mg/kg) and intravenous injection (10 mg/kg) were investigated. A rat liver microsomal model was adopted to elucidate the inhibitory effect of l-menthol on CYP1A2, CYP2C11, CYP2D1/2, CYP2D4, CYP2E1 and CYP3A1 using phenacetin, tolbutamide, omeprazole, dextromethorphan, chlorzoxazone and testosterone as probe drugs, respectively.

3. The plasma concentration reached the C_max within 1.0 h (inhalation) and descended with the T_1/2 of 8.53 and 6.69 h for inhalation and i.v. administration, respectively. IC₅₀ for inhibition of l-menthol on CYP 450 enzymes were 4.35 μM for 2D4, 8.67 μM for 1A2, 13.02 μM for 3A1, 14.78 μM for 2D1/2, 234.9 μM for 2C11 and 525.4 μM for 2E1, respectively.

4. The results illustrate the pharmacokinetic process of l-menthol in rats and provide information for further rational applications. l-Menthol had moderate inhibitions on CYP2D4 and 1A2, which might affect the disposition of medicines primarily dependent on these pathways.

Keywords:

• l-Menthol
• pharmacokinetics
• bioavailability
• inhalation
• LC–MS/MS
• cytochrome P450 enzymes

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the funds from “National Major Science and Technology Project–Prevention and Treatment of AIDS, Viral Hepatitis, and Other Major Infectious Diseases [Grant#2013ZX10005004]”, “Major Innovation Project of Science and Technology of Shandong Province [Grant#2018CSGC1411]”, “Science & Technology Enterprise Technology Innovation Fund of Jiangsu Province [Grant#BC2014172]”, “Small & Medium Enterprise Technology Innovation Project of Lianyungang City [Grant #CK1333]”.