title: Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors.
abstract: BACKGROUND
  Active renal secretion of tenofovir (TFV) across proximal tubules occurs via uptake by human organic anion transporters 1 and 3 (hOAT1 and hOAT3) coupled with efflux by multidrug resistance protein 4 (MRP4). Co-administration of some HIV protease inhibitors (PIs) with tenofovir disoproxil fumarate (TDF), an oral prodrug of TFV, has been shown to increase systemic levels of TFV, leading to a hypothesis that PIs may affect tubular secretion of TFV and potentially alter the renal safety of TDF.
  
  
  METHODS
  The effect of PIs on the transport of TFV by hOAT1, hOAT3 and MRP4 was assessed using in vitro cell-based transport models.
  
  
  RESULTS
  At concentrations equal to their therapeutic peak plasma levels (Cmax) all PIs showed <20% inhibition of TFV transport by hOAT1. hOAT3 was more sensitive to Pls with ritonavir (RTV) and lopinavir being the most potent inhibitors of TFV transport (62% and 37% inhibition, respectively, at their Cmax). In the absence of human serum, RTV at concentrations exceeding its therapeutic Cmax also exhibited a minor effect on the cellular efflux of TFV by MRP4 (<30% inhibition at 20 microM). However, no effects of PIs on hOAT1, hOAT3 or MRP4 were detected in the presence of human serum with the exception of RTV that inhibited hOAT3 by approximately 35% at its Cmax. In addition, PIs did not affect the cytotoxicity of TFV or TDF in MRP4- or MRP2-overexpressing cells.
  
  
  CONCLUSIONS
  These data indicate a low potential of PIs to interfere with the active tubular secretion of TFV and to alter the clinical renal safety profile of TDF.
authors.affiliation: Gilead Sciences, Foster City, CA, USA. tomas.cihlar@gilead.com
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.forename: Genevieve
authors.initials: G
authors.lastname: Laflamme
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Vela
authors.forename: Leah
authors.initials: L
authors.lastname: Tong
authors.forename: Michael D
authors.initials: MD
authors.lastname: Fuller
authors.forename: Anupma
authors.initials: A
authors.lastname: Roy
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Rhodes
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D016466:CHO Cells; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D063065:Organophosphonates / Q000378:metabolism* / Q000633:toxicity; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism* / Q000633:toxicity; D000068698:Tenofovir; D013997:Time Factors; D014162:Transfection
chemical_list: D000225:Adenine; D017320:HIV Protease Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; C073492:ABCC4 protein, human; C114338:organic anion transport protein 3