Pharmacokinetics-based identification of antiviral compounds of Rheum palmatum rhizomes and roots (Dahuang)

The potential of Dahuang to eliminate lung pathogens was often highlighted in Wenyi Lun. This investigation aimed to identify potential antiviral compounds of herbal component Dahuang (Rheum palmatum rhizomes and roots) of LianhuaQingwen capsule, with respect to their systemic exposure and lung reachability. Circulating Dahuang compounds were identified in human volunteers receiving LianhuaQingwen. The reachability of these compounds to SARS-CoV-2 3CLpro was assessed by in vitro transport, metabolism, immunohistochemistry, and 3CLpro-biochemical studies. LianhuaQingwen contained 55 Dahuang constituents (0.01-2.08 mol/day), categorized into eight classes. Only three compounds rhein (3), methylisorhein (10; a new Dahuang anthraquinone), and 4-O-methylgallic acid (M42M2) exhibited significant systemic exposure in humans. Two intestinal absorption mechanisms for 3 and 10 were proposed: active intestinal uptake of 3/10 by human TAUT/ASBT and human MRP1/3/4, and intestinal lacate-phlorizin hrdrolyase-mediated hydrolysis of rhein-8-O-{beta}-D-glucoside (9), followed by the transporter-mediated absorption of released 3. Targeted reachability of circulating 3/10 could be achieved as rat orthologues of human ASBT/TAUT was observed in alveolar and bronchial epithelia. These compounds exhibited potential ability to inhibit the 3CLpro enzyme responsible for coronaviral replication. Notably, Dahuang anthraquinones and tannins varied greatly in pharmacokinetics between humans and rats after dosing LianhuaQingwen. This investigation, along with such investigations of other components, has implications for precisely defining the therapeutic benefits of Dahuang-containing medicines.