DM27, an enaminone, modifies the in vitro transport of antiviral therapeutic agents

Abstract

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.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Aciclovir

“…A permeability study employing 3H‐aciclovir indicated an apparent permeability coefficient of about 1.19 × 10 −5 cm/s,53 but other reports obtained considerably lower values, ranging from of 0.12 × 10 −6 44 to 2.0 × 10 −6 cm/s,54 see Table 3. As drugs with a permeability in the range 70–100% absorbed usually have a P app value greater than 10 × 10 −6 cm/s,54 most of these data suggest that permeability of aciclovir is low.…”

Design of a graphene oxide-SnO2 nanocomposite with superior catalytic efficiency for the synthesis of β-enaminones and β-enaminoesters

“…9,10 In addition, they serve as a basic synthon for various pharmaceutical drug molecules that control physiological actions, such as anti-bacterial, 11,12 anticonvulsant, 13 antitussive, 14 anti-inammatory, 15 anti-tumor drugs. These chemicals are a highly multifaceted class of intermediates for the synthesis of heterocyclic and biologically active compounds.…”

Enaminones: Exploring Additional Therapeutic Activities

“…Additionally, 37h caused a statistically significant increase (139.2%) in cyclosporin A (CSA, a P‐gp substrate and inhibitor) transport at 10 −7 M. Since 37h proved a more potent P‐gp inhibitor than 37i , the transport of antiviral P‐gp substrates (zidovudine, saquinavir, ritonavir, amprenavir, and acyclovir) was evaluated in Caco‐2 cells and was shown to be significantly ( P < 0.05) enhanced over a range of 23.7–51.3% after 37h coincubation. The P app values for acyclovir, saquinavir, amprenavir, ritonavir, and zidovudine were statistically higher in the 37h treated group compared to the control group with ∼25%, 23.7%, 44.7%, 51.3%, and 29.4% increases, respectively 176. The effect of 37h on the transport of acyclovir and the antiretroviral agents reflected the relative differences in their efflux properties and P‐gp affinity in reference to 37h , where zidovudine (substrate for multiple transporters such as P‐gp, MRP, OATP and OAT, and nucleoside systems)177, 178 displayed maximal 37h ‐effect at 10 −4 M, while ritonavir (high affinity P‐gp substrate) displayed maximal 37h ‐effect at 10 −10 M. …”

“…Comparing 37h inhibitory effect to other P‐gp inhibitors revealed that 37h was more potent in increasing paclitaxel apical to basolateral transport [360% vs. 212.6% with 37h ( 10 −6 M) and CSA (5 × 10 −6 M), respectively] of 3.22, 2.18, and 2.48, respectively. Additionally, the unaltered transport of mannitol (paracellular marker) and propranolol (transcellular marker) suggest that the effect of 37h on paclitaxel transport was through P‐gp modulation rather than modulation to the paracellular or the transcellular routes, respectively 176…”