Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: Interactions with the neutral and cationic amino acid transporter on the corneal epithelium

Anand, Banmeet; Suresh, K.; Nashed, Yasser E.; Mitra, Ashim K.

doi:10.1080/02713680490504614

Cited by 42 publications

(53 citation statements)

References 19 publications

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“…These compounds were designed to target the transporters on the cornea and intestinal epithelial cells for improved ocular and oral absorption of acyclovir, respectively. Previous results indicated that the amino acid ester prodrugs of ACV exhibited affinity toward the amino acid transporters, and the uptake of these prodrugs was efficiently mediated by ASCT1 and B 0,+ (Anand et al, 2004b;Katragadda et al, 2008). In this report, we describe pharmacokinetics of these prodrugs after oral administration in Sprague-Dawley rats.…”

Section: Mediated Intestinal Translocationmentioning

confidence: 96%

“…A series of novel water-soluble amino acid ester prodrugs of acyclovir were synthesized previously (Anand et al, 2004b;Katragadda et al, 2008). These compounds were designed to target the transporters on the cornea and intestinal epithelial cells for improved ocular and oral absorption of acyclovir, respectively.…”

Section: Mediated Intestinal Translocationmentioning

confidence: 99%

“…The buffer components and solvents were obtained from Fisher Scientific (St. Louis, MO). All the amino acid prodrugs of acyclovir ( Figure 1) were synthesized in our laboratory according to previously published procedures (Anand et al, 2004b;Katragadda et al, 2008). Four amino acid prodrugs were used in this study: L-Alanine-ACV (AACV), L-Serine-ACV (SACV), L-Isoleucine-ACV (IACV), and γ-Glutamate-ACV (EACV).…”

Section: Mediated Intestinal Translocationmentioning

confidence: 99%

“…This method gave rapid and reproducible results. HPLC conditions for the various compounds have been described previously (Anand et al, 2004b;Katragadda et al, 2008). Intra-and interday precision (measured by coefficient of variation, CV%) was less than 3 and 5%, respectively.…”

Section: Analytical Proceduresmentioning

confidence: 99%

“…Strategies have been used to design prodrugs of various poorly absorbed drugs targeted toward receptors/transporters to improve systemic bioavailability (Anand et al, 2004a;Anand et al, 2004b;Steffansen et al, 2004;Tolle-Sander et al, 2004). Valacyclovir (VACV) is such a prodrug that is derived from acyclovir (ACV) by esterifying 3-hydroxyl group of ACV with L-valine.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: Interaction with the transporters on Caco-2 cells

Suresh¹,

Jain²,

Kwatra³

et al. 2008

International Journal of Pharmaceutics

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In vivo systemic absorption of the amino acid prodrugs of acyclovir (ACV) after oral administration was evaluated in rats. Stability of the prodrugs, L-Alanine-ACV (AACV), L-Serine-ACV (SACV), L-Isoleucine-ACV (IACV), γ-Glutamate-ACV (EACV) and L-Valine-ACV (VACV) was evaluated in various tissues. Interaction of these prodrugs with the transporters on Caco-2 cells was studied.In vivo systemic bioavailability of these prodrugs upon oral administration was evaluated in jugular vein cannulated rats. The amino acid ester prodrugs showed affinity towards various amino acid transporters as well as the peptide transporter on the Caco-2 cells. In terms of stability, EACV was most enzymatically stable compared to other prodrugs especially in liver homogenate. In oral absorption studies, ACV and AACV showed high terminal elimination rate constants (λ z ). SACV and VACV exhibited approximately five fold increase in area under the curve (AUC) values relative to ACV (p<0.05). C max(T) (maximum concentration) of SACV was observed to be 39 ± 22 µM in plasma which is 2 times better than VACV and 15 times better than ACV. C last(T) (concentration at the last time point) of SACV was observed to be 0.18 ± 0.06 µM in plasma which is 2 times better than VACV and 3 times better than ACV. Amino acid ester prodrugs of ACV were absorbed at varying amounts (C max ) and eliminated at varying rates (λ z ) thereby leading to varying extents (AUC). The amino acid ester prodrug SACV owing to its enhanced stability, higher AUC and better concentration at last time point seems to be a promising candidate for the oral treatment of herpes infections.

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Section: Mediated Intestinal Translocationmentioning

confidence: 96%

Section: Mediated Intestinal Translocationmentioning

confidence: 99%

Section: Mediated Intestinal Translocationmentioning

confidence: 99%

Section: Analytical Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: Interaction with the transporters on Caco-2 cells

Suresh¹,

Jain²,

Kwatra³

et al. 2008

International Journal of Pharmaceutics

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Injectable Pro-drugs Approach for Retina and Posterior Segment Disease

Patel

Pathak

2018

Drug Delivery for the Retina and Posterior Segment Disease

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Transcorneal Permeation of l- and d-Aspartate Ester Prodrugs of Acyclovir: Delineation of Passive Diffusion Versus Transporter Involvement

et al. 2008

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Purpose-The aim of this study was to evaluate the contribution of amino acid transporters in the transcorneal permeation of the aspartate (Asp) ester acyclovir (ACV) prodrug.Methods-Physicochemical characterization, solubility and stability of acyclovir L-aspartate (LAsp-ACV) and acyclovir D-aspartate (D-Asp-ACV) were studied. Transcorneal permeability was evaluated across excised rabbit cornea.Results-Solubility of L-Asp-ACV and D-Asp-ACV were about 2-fold higher than that of ACV. The prodrugs demonstrated greater stability under acidic conditions. Calculated pK a and logP values for both prodrugs were identical. Transcorneal permeability of L-Asp-ACV (12.1±1.48×10 −6 cm/s) was 4-fold higher than D-Asp-ACV (3.12±0.36×10 −6 cm/s) and ACV (3.25±0.56×10 −6 cm/s). ACV generation during the transport process was minimal. L-Asp-ACV transport was sodium and energy dependent but was not inhibited by glutamic acid. Addition of BCH, a specific B o,+ and L amino acid transporter inhibitor, decreased transcorneal L-Asp-ACV permeability to 2.66±0.21×10 −6 cm/ s. L-Asp-ACV and D-Asp-ACV did not demonstrate significant difference in stability in ocular tissue homogenates.Conclusion-The results demonstrate that enhanced transport of L-Asp-ACV is as a result of corneal transporter involvement (probably amino acid transporter B 0,+ ) and not as a result of changes in physicochemical properties due to prodrug derivatization (permeability of D-Asp-ACV and ACV were not significantly different).

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Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: Interactions with the neutral and cationic amino acid transporter on the corneal epithelium

Cited by 42 publications

References 19 publications

Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: Interaction with the transporters on Caco-2 cells

Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: Interaction with the transporters on Caco-2 cells

Injectable Pro-drugs Approach for Retina and Posterior Segment Disease

Transcorneal Permeation of l- and d-Aspartate Ester Prodrugs of Acyclovir: Delineation of Passive Diffusion Versus Transporter Involvement

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