title: Herb-drug interaction between an anti-HIV Chinese herbal SH formula and atazanavir in vitro and in vivo.
abstract: BACKGROUND
  With the prevalent use of highly active antiretroviral therapy (HAART) for AIDS patients since 1996, the mortality of HIV/AIDS patients has been remarkably decreased. With long-term use of HAART, drug resistance and side effects of antiretrovirals have been frequently reported, which not only reduce the efficacy, but also decreases the tolerance of patients. Traditional herbal medicine has become more popular among HIV/AIDS patients as adjuvant therapy to reduce these adverse effects of HAART. SH formula is a Chinese herbal formula consisting of five traditional Chinese herbs including Morus alba L., Glycyrrhiza glabra L., Artemisia capillaris Thumb., Astragalus membranaceus Bge., and Carthamus tinctorius L. SH formula is clinically used for HIV treatment in Thailand. However, the possible pharmacokinetic interactions between these Chinese herbs and antiretroviral drugs have not been well documented. The aim of this study was to investigate the potential herb-drug interaction between SH herbal Chinese formula and the antiretroviral drug atazanavir (ATV).
  
  
  METHODS
  The combination effect of SH formula and ATV on HIV protease was studied in HIV-1 protease inhibition assay in vitro. The inhibition of SH formula on rat CYP3A2 was assessed by detecting the formation of 1'-OH midazolam from midazolam in rat liver microsomes in vitro. The in vivo pharmacokinetic interaction between SH formula and ATV was investigated by measuring time-dependent plasma concentrations of ATV in male Sprague-Dawley rats with liquid chromatography-mass spectrometry.
  
  
  RESULTS
  Through the in vitro HIV-1 protease inhibition assay, combination of SH formula (41.7-166.7 μg/ml) and ATV (16.7-33.3 ng/ml) showed additive inhibition on HIV-1 protease activity than SH formula or ATV used alone. In vitro incubation assay indicated that SH formula showed a weak inhibition (IC50=231.2 µg/ml; Ki=98.2 µg/ml) on CYP3A2 activity in rat liver microsomes. In vivo pharmacokinetic study demonstrated that SH formula did not affect the metabolism of ATV in rats.
  
  
  CONCLUSIONS
  Our study demonstrated for the first time that there is no metabolism-based herb-drug interaction between SH formula and ATV in rats, but this combination enhances the inhibition potentials against HIV protease activity. This observation may support the combinational use of anti-HIV treatment in human.
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Bao-Hui
authors.initials: BH
authors.lastname: Cheng
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Judy Yuet-Wa
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Huang-Quan
authors.initials: HQ
authors.lastname: Lin
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Penelope M Y
authors.initials: PM
authors.lastname: Or
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: David Chi-Cheong
authors.initials: DC
authors.lastname: Wan
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Ping-Chung
authors.initials: PC
authors.lastname: Leung
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Kwok-Pui
authors.initials: KP
authors.lastname: Fung
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. Electronic address: claralau@cuhk.edu.hk.
authors.forename: Clara Bik-San
authors.initials: CB
authors.lastname: Lau
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000493:pharmacokinetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease; D041743:Herb-Drug Interactions; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013785:Thailand
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D000069446:Atazanavir Sulfate; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: Anti-HIV; Atazanavir; CYP3A2; Herb–drug interaction; SH formula