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 μmol/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 -β-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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ChiCTR1900021460 ### Funding Statement This work was funded by grants from the National Natural Science Foundation of China (Grant Nos.: 82074176 and 81503345), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (Grant No.: ZYYCXTD-C-202009), and the National Key R&D Program of China (Grant No.: 2018YFC1704500). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Hebei Yiling Hospital gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors All data produced in the present work are contained in the manuscript * 3CLpro : 3-chymotrypsin-like protease ASBT/Asbt : apical sodium-dependent bile acid transporter TAUT/Taut : taurine transporter