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Transcorneal permeation of L- and D-aspartate ester prodrugs of acyclovir: delineation of passive diffusion versus transporter involvement.
Pharm Res 2009; 26(5):1261-9PR

Abstract

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 (L-Asp-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 twofold 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 x 10(-6) cm/s) was fourfold higher than D-Asp-ACV (3.12 +/- 0.36 x 10(-6) cm/s) and ACV (3.25 +/- 0.56 x 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(0,+) and L amino acid transporter inhibitor, decreased transcorneal L-Asp-ACV permeability to 2.66 +/- 0.21 x 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).

Authors+Show Affiliations

Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, Faser Hall, University, Mississippi 38677, USA. majumso@olemiss.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18839288

Citation

Majumdar, Soumyajit, et al. "Transcorneal Permeation of L- and D-aspartate Ester Prodrugs of Acyclovir: Delineation of Passive Diffusion Versus Transporter Involvement." Pharmaceutical Research, vol. 26, no. 5, 2009, pp. 1261-9.
Majumdar S, Hingorani T, Srirangam R, et al. Transcorneal permeation of L- and D-aspartate ester prodrugs of acyclovir: delineation of passive diffusion versus transporter involvement. Pharm Res. 2009;26(5):1261-9.
Majumdar, S., Hingorani, T., Srirangam, R., Gadepalli, R. S., Rimoldi, J. M., & Repka, M. A. (2009). Transcorneal permeation of L- and D-aspartate ester prodrugs of acyclovir: delineation of passive diffusion versus transporter involvement. Pharmaceutical Research, 26(5), pp. 1261-9. doi:10.1007/s11095-008-9730-0.
Majumdar S, et al. Transcorneal Permeation of L- and D-aspartate Ester Prodrugs of Acyclovir: Delineation of Passive Diffusion Versus Transporter Involvement. Pharm Res. 2009;26(5):1261-9. PubMed PMID: 18839288.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transcorneal permeation of L- and D-aspartate ester prodrugs of acyclovir: delineation of passive diffusion versus transporter involvement. AU - Majumdar,Soumyajit, AU - Hingorani,Tushar, AU - Srirangam,Ramesh, AU - Gadepalli,Rama Sarma, AU - Rimoldi,John M, AU - Repka,Michael A, Y1 - 2008/10/07/ PY - 2008/04/30/received PY - 2008/09/12/accepted PY - 2008/10/8/pubmed PY - 2009/8/4/medline PY - 2008/10/8/entrez SP - 1261 EP - 9 JF - Pharmaceutical research JO - Pharm. Res. VL - 26 IS - 5 N2 - 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 (L-Asp-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 twofold 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 x 10(-6) cm/s) was fourfold higher than D-Asp-ACV (3.12 +/- 0.36 x 10(-6) cm/s) and ACV (3.25 +/- 0.56 x 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(0,+) and L amino acid transporter inhibitor, decreased transcorneal L-Asp-ACV permeability to 2.66 +/- 0.21 x 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). SN - 1573-904X UR - https://www.unboundmedicine.com/medline/citation/18839288/Transcorneal_permeation_of_L__and_D_aspartate_ester_prodrugs_of_acyclovir:_delineation_of_passive_diffusion_versus_transporter_involvement_ L2 - https://doi.org/10.1007/s11095-008-9730-0 DB - PRIME DP - Unbound Medicine ER -