Vitreal Pharmacokinetics of Peptide-Transporter-Targeted Prodrugs of Ganciclovir in Conscious Animals

Abstract

Purpose: To delineate the vitreal pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV) with conscious rabbit model using ocular microdialysis and to compare with published results from anesthetized model. Methods: New Zealand albino male rabbit was selected as the animal model. Conscious animal ocular microdialysis technique with permanently implanted probes was employed to delineate the pharmacokinetics of GCV, l-valine-GCV (Val-GCV), and dipeptide monoester GCV prodrugs [Val-Val and l-glycine-Val (Gly-Val)] after intravitreal administration. Results: This work employs conscious model to evaluate vitreal pharmacokinetic parameters and compares the results with previously published data from anesthetized animal, thereby demonstrating the effect of anesthesia on the vitreal disposition of dipeptide prodrugs of GCV. Results have revealed that area under curve (AUC), clearance, and last measured plasma concentration (C last ) for all 4 compounds were significantly altered in a conscious animal relative to the anesthetized model, while mean residence time (MRT) was significantly reduced. However, the AUCs of regenerated Val-GCV and GCV from Gly-Val-GCV and Val-Val-GCV were found to be unchanged, suggesting higher ocular metabolism in conscious animals. Conclusion: This study for the first time delineates the vitreal pharmacokinetics of a GCV prodrug in conscious animals and compares the data with anesthetized animals. Lower vitreal exposure levels were obtained in case of conscious animal model; however, the elimination rates were not influenced by anesthesia.

Global Expression of Molecular Transporters in the Human Vaginal Tract: Implications for HIV Chemoprophylaxis

“…Targeting molecular transporters in the VT for enhanced bioavailability may provide a powerful strategy in the rational design and selection of ARV prodrugs in topical HIV PrECP. Existing antiviral prodrugs that benefit from carrier-mediated transport to increase their oral bioavailability include the commercially available L -valyl ester of acyclovir (valacyclovir) and mono- and di-peptide prodrugs of acyclovir, ganciclovir, and saquinavir developed by Mitra and colleagues [45-48]. All these prodrugs target PEPT1 ( SLC15A1 -gene product) and, to a lesser extent, PEPT2 ( SLC15A2 -gene product), membrane transporters that were under-expressed in all samples measured here (Figure 6).…”

Transporters and receptors in the posterior segment of the eye

“…Further observations showed that uptake of biotin on TR-iBRB2 cells was Na + , temperature and concentration dependent, which was signifi cantly inhibited by substrates such as biotin, pantothenic acid, lipoic acid and desthiobiotin and with a K m of 146 μ m . Moreover, the drug-conjugated vitamin approach has also been explored to improve the drug delivery and targeting effect [113,114]. These fi ndings provide important information about our understanding of its physiological role in the transport of vitamins such as biotin, pantothenic acid and other co-factors such as lipoic acid to the inner/outer BRB and neural retina.…”

Prodrug Strategies in Ocular Drug Delivery

“…Prodrugs have been synthesized in such a way that (a) chemically modified drug will have lower affinity towards effiux transporter such as quinidine prodrugs [81-83], or (b) chemically modified drug will have higher affinity towards influx transporter which otherwise are not recognized as such by a transporter such as peptide and amino acid prodrugs (acyclovir [84-86] and ganciclovir [87-89]). Hence higher ocular bioavailability of therapeutic agents can be achieved.…”

“…Hence higher ocular bioavailability of therapeutic agents can be achieved. In addition to peptide (PepT1) [87, 90], amino acid (LAT1, LAT2, B(0,+)) [84, 91] and monocarboxylic acid (MCT) [92, 93] transporters, recently various vitamin transporters such biotin [94] and ascorbic acid (SVCT2) [95-98] have been utilized for the delivery of various ocular prodrugs.…”