title: The anthraquinone drug rhein potently interferes with organic anion transporter-mediated renal elimination.
abstract: Rhein, a major metabolite of the prodrug diacerein and a major component of the medicinal herb Rheum sp., is used for its beneficial effects in a variety of clinical applications including the treatment of osteoarthritis and diabetic nephropathy. The physicochemical properties of rhein are consistent with those of known organic anion transporter (OAT) substrates and inhibitors. Therefore, the inhibitory effect of rhein on human (h) OAT1, hOAT3, hOAT4, and murine (m) Oat1 and mOat3 was examined in heterologous cell lines stably expressing each transporter in isolation. Rhein was shown to potently inhibit hOAT1 and hOAT3, with IC50 estimates in the low nanomolar range (IC50=77.1±5.5 nM and 8.4±2.5 nM, respectively), while poor affinity was observed for hOAT4 (IC50>100 μM). Marked species differences were observed with hOAT1 and hOAT3 exhibiting 3- and 28-fold higher affinity for rhein as compared to their murine orthologs. The estimated drug-drug interaction (DDI) indices (>>0.1) indicated a very strong potential for clinically relevant, rhein perpetrated DDIs mediated by inhibition of hOAT1 (DDI index=5.0; 83% inhibition) and/or hOAT3 (DDI index=46; 98% inhibition) transport activity. These results suggested that rhein, from herbal medicines and/or prodrug conversion, may significantly impact the dosing, efficacy and toxicity (i.e., pharmacokinetics and pharmacodynamics) of co-administered hOAT1 and/or hOAT3 drug substrates.
authors: Department of Pharmaceutics, Virginia Commonwealth University, 410 N 12th Street, Richmond, VA 23298-0533, USA. Electronic address: wangl4@vcu.edu.
authors: Li
authors: L
authors: Wang
authors: Xiaolei
authors: X
authors: Pan
authors: Douglas H
authors: DH
authors: Sweet
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000493:pharmacokinetics*; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D004347:Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism; D013045:Species Specificity; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
chemical_list: D000880:Anthraquinones; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C427207:SLC22A11 protein, human; C114338:organic anion transport protein 3; D010130:p-Aminohippuric Acid; C020491:rhein
keywords: Drug–drug interaction; Nephroprotective; Rhei rhizoma; SLC22A6; SLC22A8; Solute carrier