title: Investigation on modulation of human P-gp by multiple doses of Radix Astragali extract granules using fexofenadine as a phenotyping probe.
abstract: BACKGROUND
  Herb-drug interactions may potentially affect drug efficacy and/or the likelihood of adverse drug reactions. Radix Astragali (RA) extract formulation is usually prescribed for long-term use for patients with immunodeficiency, diabetes, nephropathy or cardiovascular diseases. Its use in combination with P-glycoprotein (P-gp) substrates is possible in clinical practice. Currently there is little knowledge about whether concomitant use of RA extract has an influence on disposition of P-gp substrate.
  
  
  OBJECTIVE
  This study was to investigate whether continuous and multiple doses of RA extract granules had modulatory effects on human P-gp.
  
  
  METHODS
  A randomised, placebo-controlled, two-period crossover pharmacokinetic drug interaction study was conducted in healthy Chinese volunteers. Fexofenadine was used as a P-gp phenotyping probe. Fourteen volunteers received RA extract granules or placebo (4g bid) for 7 days and then received a single oral dose of 120mg fexofenadine. Fexofenadine plasma concentrations were determined by HPLC. Pharmacokinetic parameters were calculated by non-compartmental method and bioequivalence evaluation was performed.
  
  
  RESULTS
  Pharamcokinetic parameters in the placebo phase were as follows: T1/2 (3.75±1.47h), Cmax (745.11±137.41μg/L), Tmax (2.25±0.47h), AUC(0-t) (3894.27±923.45μgh/L), AUC(0-∞) (3993.84±912.97μgh/L). Pharamcokinetic parameters in the RA extract phase were as follows: T1/2 (4.00±1.24h), Cmax (709.44±170.03μg/L), Tmax (2.21±0.51h), AUC(0-t) (3832.72±1077.60μgh/L), AUC(0-∞) (3983.53±1019.83μgh/L). The influence of RA extract on fexofenadine Cmax and AUC lacks statistical significance. Fexofenadine in the two phases were bioequivalent. In the placebo phase, T1/2 of fexofenadine in ABCB1 3435T mutation allele carriers was longer compared to ABCB1 3435CC carriers (4.43±1.44h vs. 2.54±0.21h, p<0.05). However, RA extract pretreatment abolished such genotype-related difference due to the lengthened T1/2 in ABCB1 3435CC carriers. There was no association of the C3435T polymorphism with Cmax and AUC(0-t) in subjects with two pretreatments.
  
  
  CONCLUSIONS
  One-week administration of RA extract granules did not have a statistically significant impact on systematic exposure to fexofenadine, suggesting that RA extract is not a potent modulator of P-gp in vivo. RA extract appears to have ABCB1 C3435T genotype-dependent inhibitory effect on elimination rather than absorption of a P-gp substrate. Further investigations are necessary in patients who receive long-term use of RA extract formulation and combined P-gp substrates, especially in those ABCB1 3435CC carriers.
authors: Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China. zhouquan142602@zju.edu.cn
authors: Quan
authors: Q
authors: Zhou
authors: Zhen
authors: Z
authors: Ye
authors: Zourong
authors: Z
authors: Ruan
authors: Su
authors: S
authors: Zeng
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D027883:Astragalus Plant; D027885:Astragalus propinquus; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013379:Substrate Specificity; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004365:Drugs, Chinese Herbal; D016593:Terfenadine; C027492:Huang Qi; C093230:fexofenadine