title: HIV protease inhibitors: garlic supplements and first-pass intestinal metabolism impact on the therapeutic efficacy.
abstract: OBJECTIVE
  The aim of this study was to elucidate the impact of first-pass intestinal metabolism to therapeutic efficacy of antiretrovirals and to ascertain interaction mechanisms between garlic supplements (aged garlic extract) and HIV-protease inhibitors.
  
  
  METHODS
  In vitro permeability through rat jejunum, Caco-2 cell monolayers was determined and CYP3A4 metabolism studies were performed.
  
  
  RESULTS
  Saquinavir and darunavir efflux from enterocytes into gastrointestinal lumen significantly increased in the presence of aged garlic extract, whereas their CYP3A4 metabolism was inhibited. In the case of saquinavir a significant increase of its efflux was observed also in the presence of lower ritonavir doses. Because both drugs bound to different binding sites on P-glycoprotein and/or multidrug resistance associated protein 2 than garlic phytochemicals or ritonavir, lower amounts of antiretrovirals were absorbed.
  
  
  CONCLUSIONS
  The fractions of tested anti-HIV drugs absorbed could decrease significantly during self-medication with garlic supplements or ritonavir dose adjustments. Due to distinct saquinavir and darunavir preferences for binding sites on efflux transporters, the presence of other compounds (garlic phytochemicals, ritonavir), capable of influencing intestinal transporter-enzyme interplay, might lead to pharmacokinetic interactions observed in clinical studies and case reports with anti-HIV drugs.
authors.affiliation: Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia. katja.berginc@ffa.uni-lj.si
authors.forename: Katja
authors.initials: K
authors.lastname: Berginc
authors.forename: Tina
authors.initials: T
authors.lastname: Trdan
authors.forename: Jurij
authors.initials: J
authors.lastname: Trontelj
authors.forename: Albin
authors.initials: A
authors.lastname: Kristl
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D000069454:Darunavir; D019587:Dietary Supplements; D004347:Drug Interactions; D020895:Enterocytes / Q000378:metabolism; D005737:Garlic; D017320:HIV Protease Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010936:Plant Extracts / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019438:Ritonavir / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D019258:Saquinavir / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D013449:Sulfonamides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D051544:Cytochrome P-450 CYP3A; D000069454:Darunavir; D017320:HIV Protease Inhibitors; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010936:Plant Extracts; D019438:Ritonavir; D019258:Saquinavir; D013449:Sulfonamides; C510163:CYP3A4 protein, human