Single oral dose pharmacokinetics of decursin and decursinol angelate in healthy adult men and women

Abstract

The ethanol extract of Angelica gigas Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our in vitro metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (Tmax) of 2.1, 2.4 and 3.3 h and mean peak concentration (Cmax) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (t1/2) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h∙nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation.

Trial registration: ClinicalTrials.gov NCT02114957.

Conflict of interest statement

Competing Interests: The authors confirm that Junxuan Lu, as co-author and corresponding author, is a PLOS ONE Editorial Board member (Academic Editor) and that this does not alter the authors' adherence to PLOS ONE Editorial policies and criteria, as detailed online in guide for authors.

Figures

Fig 1. CONSORT flow diagram for single dose PK study of Cogni.Q pyranocoumarins.

Fig 2. Chemical structures of pyranocoumarins, UHPLC characterization of test material Cogni.Q and example of UHPLC analysis of a plasma sample.

a) Structure of decursin (D), decursinol angelate (DA) and decursinol (DOH); b) Chemical fingerprinting of Cogni.Q and AGN extract by UHPLC-MS/MS in full scan mode (EMS scan); c) Typical chromatograms of D, DA and DOH in human plasma by UHPLC-MS/MS in MRM mode.

Fig 3. Human plasma concentration (Cp)-time profiles of pyranocoumarins after a single oral dose of Cogni.Q.

(a) Parent compounds D and DA. (b) Product DOH. Mean ± SEM of all 20 subjects. Inserts show the semi-log plot of Cp versus time for corresponding analytes. Terminal t1/2 for D and DA was statistically the same (17.4 and 19.3 hours, respectively) and that for DOH was shorter (7.4 hours).

Fig 4. Gender comparison of plasma concentration (Cp)-time profiles of pyranocoumarins after a single oral dose of Cogni.Q.

(a) DA. (b) DOH. Mean ± SEM. Men (n = 10) and women (n = 10).