title: DM27, an enaminone, modifies the in vitro transport of antiviral therapeutic agents.
abstract: OBJECTIVE
  For most antiviral drugs, low or variable bioavailability is attributed to poor absorption, susceptibility to efflux, or first pass metabolism. Enaminones are beta dicarbonyl compounds, which display P-glycoprotein (P-gp) substrate properties with high efflux ratios. This study investigates the influence of DM27, an enaminone, on the in vitro transport of antiviral agents and the possibility of using DM27 as a P-gp inhibitor to prevent the efflux of certain antiretroviral agents.
  
  
  METHODS
  The transport of [3H]amprenavir, [3H]saquinavir, [3H]ritonavir, [14C]zidovudine (AZT) and [3H]acyclovir was evaluated across Caco-2 cells with DM27 (10(-10)-10(-4) M). In addition, the effect of DM27 (10(-6) M) on the transport of transcellular and paracellular markers was tested to evaluate its influence on these transport pathways. The apparent permeability coefficient (Papp) for each drug or marker was calculated with/without DM27 and toxicity evaluation for DM27 was performed using the MTS assay.
  
  
  RESULTS
  The mean Papp for the investigated antiviral agents significantly increased by 22%-51% after DM27 incubation without any toxicity to the Caco-2 cells. In addition, DM27 did not influence the transcellular or paracellular transport of propranolol and mannitol, respectively.
  
  
  CONCLUSIONS
  DM27, an enaminone, increased the transport of antiretroviral drugs and acyclovir in a nontoxic manner without affecting the paracellular or transcellular transport of these drugs. This study suggests that DM27 may be used as a P-gp efflux inhibitor to enhance the oral bioavailability of antiviral drugs and that drug-drug interactions will most probably be encountered upon co-administration of P-gp substrate drugs with enaminones.
authors.affiliation: Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, Baltimore, MD 21201, USA.
authors.forename: Noha N
authors.initials: NN
authors.lastname: Salama
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Scott
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Eddington
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D003510:Cyclohexanes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003512:Cyclohexanones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans
chemical_list: C495413:3-(N-(4-chlorophenyl)amino)-5-methyl-2-cyclohexenone; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000998:Antiviral Agents; D003510:Cyclohexanes; D003512:Cyclohexanones