title: Evaluation of the transporter-mediated herb-drug interaction potential of DA-9801, a standardized dioscorea extract for diabetic neuropathy, in human in vitro and rat in vivo.
abstract: BACKGROUND
  Drug transporters play important roles in the absorption, distribution, and elimination of drugs and thereby, modulate drug efficacy and toxicity. With a growing use of poly pharmacy, concurrent administration of herbal extracts that modulate transporter activities with drugs can cause serious adverse reactions. Therefore, prediction and evaluation of drug-drug interaction potential is important in the clinic and in the drug development process. DA-9801, comprising a mixed extract of Dioscoreae rhizoma and Dioscorea nipponica Makino, is a new standardized extract currently being evaluated for diabetic peripheral neuropathy in a phase II clinical study.
  
  
  METHODS
  The inhibitory effects of DA-9801 on the transport functions of organic cation transporter (OCT)1, OCT2, organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) were investigated in HEK293 or LLC-PK1 cells. The effects of DA-9801 on the pharmacokinetics of relevant substrate drugs of these transporters were also examined in vivo in rats.
  
  
  RESULTS
  DA-9801 inhibited the in vitro transport activities of OCT1, OCT2, OAT3, and OATP1B1, with IC50 values of 106, 174, 48.1, and 273 μg/mL, respectively, while the other transporters were not inhibited by 300 μg/mL DA-9801. To investigate whether this inhibitory effect of DA-9801 on OCT1, OCT2, and OAT3 could change the pharmacokinetics of their substrates in vivo, we measured the pharmacokinetics of cimetidine, a substrate for OCT1, OCT2, and OAT3, and of furosemide, a substrate for OAT1 and OAT3, by co-administration of DA-9801 at a single oral dose of 1,000 mg/kg. Pre-dose of DA-9801 5 min or 2 h prior to cimetidine administration decreased the Cmax of cimetidine in rats. However, DA-9801 did not affect the elimination parameters such as half-life, clearance, or amount excreted in the urine, suggesting that it did not inhibit elimination process of cimetidine, which is governed by OCT1, OCT2, and OAT3. Moreover, DA-9801 did not affect the pharmacokinetic characteristics of furosemide, as evidenced by its unchanged pharmacokinetic parameters.
  
  
  CONCLUSIONS
  Inhibitory effects of DA-9801 on OCT1, OCT2, and OAT3 observed in vitro may not necessarily translate into in vivo herb-drug interactions in rats even at its maximum effective dose.
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
authors.forename: Tae Yeon
authors.initials: TY
authors.lastname: Kong
authors.forename: Hyeon-Uk
authors.initials: HU
authors.lastname: Jeong
authors.forename: Eun Nam
authors.initials: EN
authors.lastname: Kim
authors.forename: Soon-Sang
authors.initials: SS
authors.lastname: Kwon
authors.forename: Hee Eun
authors.initials: HE
authors.lastname: Kang
authors.forename: Sang-Zin
authors.initials: SZ
authors.lastname: Choi
authors.forename: Miwon
authors.initials: M
authors.lastname: Son
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea. sianalee@catholic.ac.kr.
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000818:Animals; D002927:Cimetidine / Q000493:pharmacokinetics*; D005665:Furosemide / Q000097:blood / Q000493:pharmacokinetics*; D057809:HEK293 Cells; D041743:Herb-Drug Interactions; D006801:Humans; D008297:Male; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D028321:Plant Preparations / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C562027:DA-9801; D027701:Organic Cation Transport Proteins; D028321:Plant Preparations; D005665:Furosemide; D002927:Cimetidine