Pharmacokinetics of major indigo naturalis indole alkaloids in humans and their association with systemic aryl hydrocarbon receptor activity

Indigo naturalis (IN) is a natural product extensively used as a traditional Chinese medicine due to its pharmacological properties. While IN has been proposed to exert its activity, at least partly, via the Aryl Hydrocarbon Receptor (AhR), the pharmacokinetics of its known indole alkaloid AhR ligands and their relative contributions to the net AhR agonistic activity in blood is unknown. We conducted an open-label, placebo-controlled, dose-escalation study (0.25-2.0 g) of orally-administered IN in healthy individuals. Blood samples obtained prior and up to 24 h after ingestion were analysed for net AhR activity and pharmacokinetics of circulating IN-derived AhR ligands determined by HPLC-ESI-MS/MS. Oral administration of IN dose-dependently increased net plasma AhR agonistic activity - initially through the early appearance of tryptanthrin, and later sustained by the more potent AhR agonist indirubin. This first pharmacokinetic study of IN-derived Indole Alkaloids in humans indicates that the increase in systemic AhR agonistic activity is the result of sequential appearance in blood of highly bioavailable / moderately agonistic (tryptanthrin) and moderately bioavailable / highly agonistic (indirubin and indigo) AhR ligands, challenging the commonly held belief that only highly agonistic Indole Alkaloids contribute to AhR agonism and therapeutic activity of IN.

Aryl hydrocarbon receptor (AhR); Dose-escalation study; Indigo naturalis; Indole alkaloids; Pharmacokinetics; Xenobiotics.