Banmeet S. Anand

Mechanism of Corneal Permeation of L-Valyl Ester of Acyclovir: Targeting the Oligopeptide Transporter on the Rabbit Cornea

AbstractPurpose. To delineate mechanisms associated with the corneal transport of a L-valine prodrug of an antiviral agent, acyclovir. Method. The permeability and enzymatic hydrolysis of L-Val-ACV were evaluated using freshly excised rabbit cornea. Transport mechanism across rabbit cornea was investigated through a competitive inhibition study of L-Val-ACV with other substrates of human peptide transporter (hPepT1). Results. L-Valyl ester of Acyclovir (L-Val-ACV) was approximately threefold more permeable across the intact rabbit cornea than acyclovir (ACV). Dipeptides, β-lactam antibiotics, and angiotensin converting enzyme (ACE) inhibitors, strongly inhibited the transport of L-Val-ACV indicating that a carrier mediated transport system specific for peptides is primarily responsible for the corneal permeation of L-Val-ACV. L-Val-ACV transport was found to be saturable (Km = 2.26 ± 0.34 mM, Jmax = 1.087 ± 0.05 nmoles cm−2 min−1), energy and pH dependent. Conclusions. Functional evidence of an oligopeptide transport system present on the rabbit cornea has been established. The peptide transporter on the corneal epithelium may be targeted to improve the ocular bioavailability of poorly absorbed drugs.

Current prodrug strategies via membrane transporters/receptors

Prodrug design strategies have been employed to improve the delivery of drugs with undesirable pharmacokinetic properties such as chemical stability and lack of specificity. Targeted prodrug design represents a new strategy for site-directed and efficient drug delivery. Targeting of drugs to transporters and receptors to aid in site-specific carrier-mediated absorption is emerging as a novel and clinically significant approach. Various prodrugs have been successful in achieving the goals of enhanced bioavailability and are, therefore, considered to be an important tool in biopharmaceutics. This review highlights the advances in prodrug design targeted towards membrane transporters/receptors in the past few years.

Novel dipeptide prodrugs of acyclovir for ocular herpes infections: Bioreversion, antiviral activity and transport across rabbit cornea

Purpose. A series of dipeptide prodrugs of antiviral nucleoside acyclovir (ACV) were designed to target the oligopeptide transporter on the cornea with an aim of improving the ocular bioavailability and therapeutic activity of ACV. Methods. Aqueous stability, ocular bioreversion kinetics in various tissues, in vitro antiviral activity, cell proliferation assay and corneal transport characteristics of the dipeptide prodrugs were studied. Results. ACV dipeptide prodrugs were found to be more stable at pH 5.6 in comparison to L-Val-ACV, an amino acid prodrug of ACV. The prodrugs exhibited higher solubility than ACV. Val-Val-ACV and Val-Tyr-ACV were found to have excellent antiviral activity against herpes simplex virus-1 (HSV-1). All the dipeptide prodrugs exhibited lower cytotoxicity as compared to currently approved anti-HSV agent, trifluorothymidine (TFT). Transport of [ 3 H] Val-ACV was inhibited significantly in the presence of the dipeptide prodrugs of ACV. Corneal permeabilities of all the ACV dipeptide prodrugs were observed to be higher than ACV possibly due to recognition of the prodrugs by the oligopeptide transporter on the cornea. Conclusions. The dipeptide prodrugs were found to be more permeable than the parent drug, ACV. More permeable, less cytotoxic ACV dipeptide prodrugs exhibited excellent chemical stability and antiviral activity against herpes simplex virus thereby rendering these lead compounds promising drug candidates against herpes virus infections.

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

Purpose. The aim of this study was to explore the feasibility of improvement of ocular bioavailability of the antiviral agent acyclovir by designing amino acid prodrugs targeted to the amino acid transporters on the rabbit cornea. Materials and methods. Transcorneal flux of two water-soluble amino acid ester prodrugs of acyclovir (ACV), γ-glutamate-ACV (EACV) and L-tyrosine-ACV (YACV), was studied across freshly excised rabbit cornea. Chemical and enzymatic hydrolysis studies of the two prodrugs were also conducted. Results. EACV inhibited the uptake of [3H]L-Arg in rabbit primary corneal epithelial cells (rPCECs). The compound also exhibited longer half-life (t1/2) in cornea in comparison to YACV. Transcorneal flux of EACV was observed to be concentration-, energy-, and sodium-dependent and independent of pH within the range studied. EACV transport was inhibited by neutral and cationic amino acids, L-ornithine (specific for cationic amino acids), and BCH (2-aminobicyclo-[2,2,1]-heptane-2-carboxylic-acid) (specific inhibitor for L-type system and B0,+ system). On the other hand, YACV was not recognized by this amino acid transporter as it failed to inhibit the uptake of [3H]Arg, and also its transport across cornea was not inhibited by arginine. YACV and EACV exhibited excellent antiviral activity against HSV-1 and 2 and Varicella-Zoster Virus (VZV) in comparison to ACV. Conclusions. Analyses of the inhibition pattern of EACV transport suggests the involvement of a single transport system; namely, B0,+. Design of amino acid prodrugs seems to be an attractive strategy to enhance the solubility of the otherwise poorly aqueous soluble compounds and also to afford a targeted and possibly enhanced delivery of the active drug.

Drug Delivery to the Eye

Publisher Summary This chapter provides a general insight into the past, present, and future trends in the area of ocular drug delivery. The chapter also presents a discussions on ocular barriers to drug delivery, modes of drug administration to the eye, effect of ocular fluid dynamics, transporter targeted drug delivery, and strategies to exploit transporters in enhancing ocular drug bioavailability. Ocular pathologies can cause discomfort and anxiety in patients, with the ultimate fear of loss of vision or even facial disfigurement. In spite of the continued effort directed toward the improvement and optimization of ocular drug delivery systems a progress in this area did not appear to take place at a fast pace that is typical of other delivery routes—oral, transdermal, and transmucosal. A cautious advancement is evidently imposed by the delicate nature of the eye and many restraints imposed by its anatomy and physiology.

Transporters/receptors in the anterior chamber: pathways to explore ocular drug delivery strategies

Membrane transporters/receptors are involved in drug transport processes and play a key role in intestinal absorption, tissue distribution and elimination. Drug targeting to specific transporters and receptors using carrier-mediated absorption has immense clinical significance. Ocular drug delivery is a challenging task since it involves drug transport across various barriers in the eye. Specialised transport processes exist at these barriers, which control the entry of drugs and xenobiotics. Ocular drug therapy involving topical or systemic administration of drugs has various limitations. Transport processes in the eye have been targeted in an effort to increase ocular bioavailability of drugs following topical instillation. This review discusses various transport processes in the eye and drug delivery strategies utilising these transporters/receptors.