Tags

Type your tag names separated by a space and hit enter

Simultaneous modulation of transport and metabolism of acyclovir prodrugs across rabbit cornea: An approach involving enzyme inhibitors.
Int J Pharm 2006; 320(1-2):104-13IJ

Abstract

The aim of this study is to identify the class of enzymes responsible for the hydrolysis of amino acid and dipeptide prodrugs of acyclovir (ACV) and to modulate transport and metabolism of amino acid and dipeptide prodrugs of acyclovir by enzyme inhibitors across rabbit cornea. l-Valine ester of acyclovir, valacyclovir (VACV) and l-glycine-valine ester of acyclovir, gly-val-acyclovir (GVACV) were used as model compounds. Hydrolysis studies of VACV and GVACV in corneal homogenate were conducted in presence of various enzyme inhibitors. IC(50) values were determined for the enzyme inhibitors. Transport studies were conducted with isolated rabbit corneas at 34 degrees C. Complete inhibition of VACV hydrolysis was observed in the presence of Pefabloc SC (4-(2-aminoethyl)-benzenesulfonyl-fluoride) and PCMB (p-chloromercuribenzoic acid). Similar trend was also observed with GVACV in the presence of bestatin. IC(50) values of PCMB and bestatin for VACV and GVACV were found to be 3.81+/-0.94 and 0.34+/-0.08muM respectively. Eserine, tetraethyl pyrophosphate (TEPP) and diisopropyl fluorophosphate (DFP) also produced significant inhibition of VACV hydrolysis. Transport of VACV and GVACV across cornea showed decreased metabolic rate and modulation of transport in presence of PCMB and bestain respectively. The principle enzyme classes responsible for the hydrolysis of VACV and GVACV were carboxylesterases and aminopeptidases respectively. Enzyme inhibitors modulated the transport and metabolism of prodrugs simultaneously even though their affinity towards prodrugs was distinct. In conclusion, utility of enzyme inhibitors to modulate transport and metabolism of prodrugs appears to be promising strategy for enhancing drug transport across cornea.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110-2499, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

16720085

Citation

Katragadda, Suresh, et al. "Simultaneous Modulation of Transport and Metabolism of Acyclovir Prodrugs Across Rabbit Cornea: an Approach Involving Enzyme Inhibitors." International Journal of Pharmaceutics, vol. 320, no. 1-2, 2006, pp. 104-13.
Katragadda S, Talluri RS, Mitra AK. Simultaneous modulation of transport and metabolism of acyclovir prodrugs across rabbit cornea: An approach involving enzyme inhibitors. Int J Pharm. 2006;320(1-2):104-13.
Katragadda, S., Talluri, R. S., & Mitra, A. K. (2006). Simultaneous modulation of transport and metabolism of acyclovir prodrugs across rabbit cornea: An approach involving enzyme inhibitors. International Journal of Pharmaceutics, 320(1-2), pp. 104-13.
Katragadda S, Talluri RS, Mitra AK. Simultaneous Modulation of Transport and Metabolism of Acyclovir Prodrugs Across Rabbit Cornea: an Approach Involving Enzyme Inhibitors. Int J Pharm. 2006 Aug 31;320(1-2):104-13. PubMed PMID: 16720085.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simultaneous modulation of transport and metabolism of acyclovir prodrugs across rabbit cornea: An approach involving enzyme inhibitors. AU - Katragadda,Suresh, AU - Talluri,Ravi S, AU - Mitra,Ashim K, Y1 - 2006/05/23/ PY - 2006/02/27/received PY - 2006/04/08/revised PY - 2006/04/17/accepted PY - 2006/5/25/pubmed PY - 2006/12/9/medline PY - 2006/5/25/entrez SP - 104 EP - 13 JF - International journal of pharmaceutics JO - Int J Pharm VL - 320 IS - 1-2 N2 - The aim of this study is to identify the class of enzymes responsible for the hydrolysis of amino acid and dipeptide prodrugs of acyclovir (ACV) and to modulate transport and metabolism of amino acid and dipeptide prodrugs of acyclovir by enzyme inhibitors across rabbit cornea. l-Valine ester of acyclovir, valacyclovir (VACV) and l-glycine-valine ester of acyclovir, gly-val-acyclovir (GVACV) were used as model compounds. Hydrolysis studies of VACV and GVACV in corneal homogenate were conducted in presence of various enzyme inhibitors. IC(50) values were determined for the enzyme inhibitors. Transport studies were conducted with isolated rabbit corneas at 34 degrees C. Complete inhibition of VACV hydrolysis was observed in the presence of Pefabloc SC (4-(2-aminoethyl)-benzenesulfonyl-fluoride) and PCMB (p-chloromercuribenzoic acid). Similar trend was also observed with GVACV in the presence of bestatin. IC(50) values of PCMB and bestatin for VACV and GVACV were found to be 3.81+/-0.94 and 0.34+/-0.08muM respectively. Eserine, tetraethyl pyrophosphate (TEPP) and diisopropyl fluorophosphate (DFP) also produced significant inhibition of VACV hydrolysis. Transport of VACV and GVACV across cornea showed decreased metabolic rate and modulation of transport in presence of PCMB and bestain respectively. The principle enzyme classes responsible for the hydrolysis of VACV and GVACV were carboxylesterases and aminopeptidases respectively. Enzyme inhibitors modulated the transport and metabolism of prodrugs simultaneously even though their affinity towards prodrugs was distinct. In conclusion, utility of enzyme inhibitors to modulate transport and metabolism of prodrugs appears to be promising strategy for enhancing drug transport across cornea. SN - 0378-5173 UR - https://www.unboundmedicine.com/medline/citation/16720085/Simultaneous_modulation_of_transport_and_metabolism_of_acyclovir_prodrugs_across_rabbit_cornea:_An_approach_involving_enzyme_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(06)00334-6 DB - PRIME DP - Unbound Medicine ER -