SYNTHESIS AND EVALUATION OF AMINO ACID ESTER CONJUGATES OF HIV PROTEASE INHIBITOR

  • CHABUKSWAR AR Mehta Department of Pharmaceutical Chemistry, MAEER’s Maharashtra Institute of Pharmacy, Pune, Maharashtra, India.
  • PREETI M. GANDHI Department of Pharmaceutical Chemistry, JSPM’s Jayawantrao Sawant College of Pharmacy and Research, Pune, Maharashtra, India.

Abstract

Objective: Ester conjugates of HIV protease inhibitor, lopinavir (LP) with various amino acids were synthesized to improve its physicochemical and pharmacokinetic profile and consequently therapeutic potential.


Materials and Methods: Conjugates of LP with amino acids; glycine, alanine, valine, and serine were prepared by dicyclohexylcarbodiimide coupling method. The synthesized compounds were characterized by nuclear magnetic resonance, mass, and Fourier-transform infrared spectroscopy and evaluated for their solubility, partition coefficient, hydrolytic stability, cytotoxicity, and permeability through Caco-2 cells.


Results: Aqueous solubility studies indicated significantly better solubility profiles of all conjugates as compared to LP. With respect to hydrolysis, all the conjugates displayed higher stability under acidic conditions while undergo hydrolysis with rise in pH. Conjugates did not exhibit cytotoxicity for concentration as high as 100 μg/ml, which indicates promising therapeutic potential. Absorptive diffusion of drug across Caco-2 cell monolayers was improved by amino acid conjugation.


Conclusion: Amino acid ester conjugates of LP not only showed better solubility but also significantly higher permeability than LP. Thus, direct conjugation of L-amino acids is a viable approach to improve oral absorption and thereby oral bioavailability of protease inhibitors.

Keywords: Amino acids,, Conjugates,, HIV,, Hydrolysis,, Lopinavir,, Solubility.

References

1. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: A review of its use in the management of HIV infection. Drugs 2003;63:769-802.
2. Tippabhotla SK, Thudi NR, Raghuvanshi R, Khuroo AH, Gurule S, Mishra S, et al. A bioequivalence study comparing two formulations of lopinavir/ritonavir capsules. Int J Clin Pharmacol Ther 2008;46:204-10.
3. Hsu A, Isaacson J, Brun S, Bernstein B, Lam W, Bertz R, et al.\ Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virusinfected patients. Antimicrob Agents Chemother 2003;47:350-9.
4. Agarwal S, Pal D, Mitra AK. Both P-gp and MRP2 mediate transport of lopinavir, a protease inhibitor. Int J Pharm 2007;339:139-47.
5. Kumar GN, Jayanti VK, Johnson MK, Uchic J, Thomas S, Lee RD, et al. Metabolism and disposition of the HIV-1 protease inhibitor lopinavir (ABT-378) given in combination with ritonavir in rats, dogs, and humans. Pharm Res 2004;21:1622-30.
6. Kumar GN, Dykstra J, Roberts EM, Jayanti VK, Hickman D, Uchic J, et al. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug interaction. Drug Metab Dispos 1999;27:902-8.
7. Johnson M, Grinsztejn B, Rodriguez C, Coco J, DeJesus E, Lazzarin A, et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ ritonavir in patients experiencing multiple virological failures. AIDS 2005;19:685-94.
8. Ribera E, Azuaje C, Lopez RM, Diaz M, Feijoo M, Pou L, et al. Atazanavir and lopinavir/ritonavir: Pharmacokinetics, safety and efficacy of a promising double-boosted protease inhibitor regimen. AIDS 2006;20:1131-9.
9. Shafran SD, Mashinter LD, Roberts SE. The effect of low-doseritonavir monotherapy on fasting serum lipid concentrations. HIV Med 2005;6:421-5.
10. Agarwal S, Boddu SH, Jain R, Samanta S, Pal D, Mitra AK, et al.Peptide prodrugs: Improved oral absorption of lopinavir, a HIV protease
inhibitor. Int J Pharm 2008;359:7-14.
11. Patel M, Mandava N, Gokulgandhi M, Pal D, Mitra AK. Amino acid prodrugs: An approach to improve the absorption of HIV-1 protease inhibitor, lopinavir. Pharmaceuticals (Basel) 2014;7:433-52.
12. Dias C, Nashed Y, Atluri H, Mitra A. Ocular penetration of acyclovir and its peptide prodrugs valacyclovir and val-valacyclovir following systemic administration in rabbits: An evaluation using ocular microdialysis and LC-MS. Curr Eye Res 2002;25:243-52.
13. Patel K, Trivedi S, Luo S, Zhu X, Pal D, Kern ER, et al. Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir. Int J Pharm 2005;305:75-89.
14. Gunda S, Hariharan S, Mitra AK. Corneal absorption and anterior chamber pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV): In vivo comparative evaluation of these prodrugs with val-GCV and GCV in rabbits. J Ocul Pharmacol Ther 2006;22:465-76.
15. Majumdar S, Nashed YE, Patel K, Jain R, Itahashi M, Neumann DM, et al. Dipeptide monoester ganciclovir prodrugs for treating HSV-1- induced corneal epithelial and stromal keratitis: In vitro and in vivo evaluations. J Ocul Pharmacol Ther 2005;21:463-74.
16. Jain R, Duvvuri S, Kansara V, Mandava NK, Mitra AK. Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats. Int JPharm 2007;336:233-40.
17. Gupta SV. Enhancing the intestinal membrane permeability of zanamivir: A carrier mediated prodrug approach. Mol. Pharm 2011;8:2358-67.
18. Urendran V, Singh A, Sampathkumar PK. Synthesis and characterization of novel amino acid prodrug of famotidine. Int J Pharm Pharm Sci
2015;7:403-8.
19. Mahfouz NM, Hassan MA. Synthesis, chemical and enzymatic hydrolysis and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility. J Pharm Pharmacol 2001;53:841-48.
20. Shah N, Seth AK, Balaraman R. Bioavailability enhancement of poorlysoluble raloxifene by designing inclusion complex with ?–cyclodextrin. Int J Pharm Pharm Sci 2015;7:205-11.
21. Aggarwal AK, Gupta M. Solubility and solution stability studies of different amino acid prodrugs of bromhexine. Drug Dev Ind Pharm 2012;38:1319-27.
22. Zhao X, Tao X, Wei D, Song Q. Pharmacological activity and hydrolysis behavior of novel ibuprofen glucopyranoside conjugates. Eur J Med Chem 2006;41:1352-8.
23. Dhokchawle BV, Bhandari AB. Synthesis, hydrolysis kinetics and pharmacological evaluation of aceclofenac prodrugs. Antiinflamm
Antiallergy Agents Med Chem 2015;13:188-94.
24. Joshi G, Kumar A, Sawant K. Bioavailability enhancement, caco- 2 cells uptake and intestinal transport of orally administered lopinavirloadedPLGA nanoparticles. Drug Deliv 2016;23:3492-504.
25. Senanayake TH, Warren G, Wei X, Vinogradov SV. Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates. J Control Release2013;167:200-9.
Statistics
161 Views | 38 Downloads
How to Cite
Mehta, C. A., and PREETI M. GANDHI. “SYNTHESIS AND EVALUATION OF AMINO ACID ESTER CONJUGATES OF HIV PROTEASE INHIBITOR”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 12, no. 6, May 2019, pp. 342-6, https://innovareacademics.in/journals/index.php/ajpcr/article/view/33521.
Section
Original Article(s)