DM27, an enaminone, modifies the in vitro transport of antiviral therapeutic agents.
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.
Salama
Noha N
NN
Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, Baltimore, MD 21201, USA.
Scott
Kenneth R
KR
Eddington
Natalie D
ND
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
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