title: Cumulative organic anion transporter-mediated drug-drug interaction potential of multiple components in salvia miltiorrhiza (danshen) preparations.
abstract: OBJECTIVE
  To evaluate organic anion transporter-mediated drug-drug interaction (DDI) potential for individual active components of Danshen (Salvia miltiorrhiza) vs. combinations using in vitro and in silico approaches.
  
  
  METHODS
  Inhibition profiles for single Danshen components and combinations were generated in stably-expressing human (h)OAT1 and hOAT3 cells. Plasma concentration-time profiles for compounds were estimated from in vivo human data using an i.v. two-compartment model (with first-order elimination). The cumulative DDI index was proposed as an indicator of DDI potential for combination products. This index was used to evaluate the DDI potential for Danshen injectables from 16 different manufacturers and 14 different lots from a single manufacturer.
  
  
  RESULTS
  The cumulative DDI index predicted in vivo inhibition potentials, 82% (hOAT1) and 74% (hOAT3), comparable with those observed in vitro, 72 ± 7% (hOAT1) and 81 ± 10% (hOAT3), for Danshen component combinations. Using simulated unbound Cmax values, a wide range in cumulative DDI index between manufacturers, and between lots, was predicted. Many products exhibited a cumulative DDI index > 1 (50% inhibition).
  
  
  CONCLUSIONS
  Danshen injectables will likely exhibit strong potential to inhibit hOAT1 and hOAT3 function in vivo. The proposed cumulative DDI index might improve prediction of DDI potential of herbal medicines or pharmaceutical preparations containing multiple components.
authors: Department of Pharmaceutics, Virginia Commonwealth University, 410 N 12th Street, Richmond, Virginia, 23298-0533, USA.
authors: Li
authors: L
authors: Wang
authors: Jürgen
authors: J
authors: Venitz
authors: Douglas H
authors: DH
authors: Sweet
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D004337:Drug Carriers; D004347:Drug Interactions; D004365:Drugs, Chinese Herbal / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007267:Injections; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D027561:Salvia miltiorrhiza / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D004365:Drugs, Chinese Herbal; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; C028972:dan-shen root extract