title: Pharmacokinetic interactions between 20(S)-ginsenoside Rh2 and the HIV protease inhibitor ritonavir in vitro and in vivo.
abstract: OBJECTIVE
  20(S)-Ginsenoside Rh2 (Rh2) has shown potent inhibition on P-glycoprotein (P-gp), while most HIV protease inhibitors are both substrates and inhibitors of P-gp and CYP3A4. The aim of this study was to investigate the potential pharmacokinetic interactions between Rh2 and the HIV protease inhibitor ritonavir.
  
  
  METHODS
  The effects of Rh2 on the cellular accumulation and transepithelial transport of ritonavir were studied in Caco-2 and MDCK-MDR1 cells. Male rats were administered Rh2 (25 or 60 mg/kg, po) or Rh2 (5 mg/kg, iv), followed by ritonavir (25 mg/kg, po). The P-gp inhibitors verapamil (20 mg/kg, po) or GF120918 (5 mg/kg, po) were used as positive controls. The concentrations of ritonavir in plasma, bile, urine, feces and tissue homogenates were analyzed using LC-MS.
  
  
  RESULTS
  Rh2 (10 μmol/L) significantly increased the accumulation and inhibited the efflux of ritonavir in Caco-2 and MDCK-MDR1 cells, as verapamil did. But Rh2 did not significantly alter ritonavir accumulation or transport in MDCK-WT cells. Intravenous Rh2 significantly increased the plasma exposure of ritonavir while reducing its excretion in the bile, and oral verapamil or GF120918 also increased plasma exposure of ritonavir but without changing its excretion in the bile. Interestingly, oral Rh2 at both doses did not significantly change the plasma profile of ritonavir. Moreover, oral Rh2 (25 mg/kg) significantly elevated the ritonavir concentration in the hepatic portal vein, and markedly increased its urinary excretion and tissue distribution, which might counteract the elevated absorption of ritonavir.
  
  
  CONCLUSIONS
  Rh2 inhibits the efflux of ritonavir through P-gp in vitro. The effects of Rh2 on ritonavir exposure in vivo depend on the administration route of Rh2: intravenous, but not oral, administration of Rh2 significantly increased the plasma exposure of ritonavir.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.forename: Bei
authors.initials: B
authors.lastname: Cao
authors.forename: Wei-Bin
authors.initials: WB
authors.lastname: Zha
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Wu
authors.forename: Lin-Sheng
authors.initials: LS
authors.lastname: Liu
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Xiao
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Gu
authors.forename: Run-Bin
authors.initials: RB
authors.lastname: Sun
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Yu
authors.forename: Tian
authors.initials: T
authors.lastname: Zheng
authors.forename: Meng-Jie
authors.initials: MJ
authors.lastname: Li
authors.forename: Xin-Wen
authors.initials: XW
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Yong
authors.initials: Y
authors.lastname: Mao
authors.forename: Chun
authors.initials: C
authors.lastname: Ge
authors.forename: Ting
authors.initials: T
authors.lastname: Ma
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Xia
authors.forename: Ji-Ye
authors.initials: JY
authors.lastname: Aa
authors.forename: Guang-Ji
authors.initials: GJ
authors.lastname: Wang
authors.forename: Chang-Xiao
authors.initials: CX
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002853:Chromatography, Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D036145:Ginsenosides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017208:Rats, Wistar; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014018:Tissue Distribution; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D036145:Ginsenosides; D017320:HIV Protease Inhibitors; D044005:Tetrahydroisoquinolines; C055305:ginsenoside Rh2; D014700:Verapamil; C083501:Elacridar; D019438:Ritonavir
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