Involvement of Multiple Transporters within the Oral Absorption of Glycoside Analogues
Received: 03-Aug-2022 / Manuscript No. jpet-22-72102 / Editor assigned: 05-Aug-2022 / PreQC No. jpet-22-72102 / Reviewed: 19-Aug-2022 / QC No. jpet-22-72102 / Revised: 24-Aug-2022 / Manuscript No. jpet-22-72102 / Published Date: 29-Aug-2022 QI No. / jpet-22-72102
Abstract
Nucleoside analogues square measure 1st line therapy in numerous severe maladies: AIDS (acquired immunological disorder disease syndrome), herpes virus infections, cancer, etc. However, several glycoside analogues exhibit poor oral bioavailability attributable to their high polarity and low viscous porousness. so as to urge around this disadvantage, prodrugs are utilised to enhance lipophility by chemical modification of the parent drug. As an alternative, prodrugs targeting transporters gift within the gut are applied to market the transport of the glycoside analogues [1]. Valacyclovir and valacyclovir square measure 2 classic essential amino acid organic compound prodrugs transported by oligopeptide transporter one. The perfect prodrug achieves delivery of a parent drug by attaching a non-toxic moiety that's stable throughout transport, however is quickly degraded to the parent drug once at the target. This text presents advances of prodrug approaches for enhancing oral absorption of glycoside analogues. Within the gift work, we have a tendency to delineate the synthesis, antiviral profiles and metabolic stability in human plasma of compound half-dozen, a possible carbonate prodrug of HIV-1 NNRTI drug candidate RDEA427. Compound half-dozen was found to inhibit the wild-type (WT) and K103N/Y181C double mutant HIV-1 strains at Nano- and submicromolar concentrations, severally [2].
Keywords
Nucleoside analogues; Oral bioavailability; Prodrug
Introduction
Nucleoside analogues square measure artificial compounds that square measure structurally kind of like natural nucleosides and, as such, square measure building blocks of nucleic acids. They act either as inhibitors of cellular and infective agent deoxyribonucleic acid and polymer polymerases or as chain terminators by incorporating into a growing deoxyribonucleic acid or polymer strand. Natural nucleosides square measure concerned in the majority cellular processes and plays a primary role in structural, energetic, regulative and metabolic functions. Hence, several glycoside analogues have cellular toxicity with efficiency against bacterium, fungi, yeast, viruses or growth tissues that is attributed to their organic chemistry mode action. Currently, glycoside analogues square measure imagined to be medication that square measure given in 1st attention in several serious malady’s like no heritable immunological disorder disease syndrome (AIDS), hepatitis, cancer, herpes, smallpox, etc. [3]. Of the about forty antiviral medication formally approved to be used, 0.5 square measure glycoside or ester analogues. Glycoside medication typically should be phosphorylated to the corresponding triphosphates by intracellular or infective agent kinases so as to exert their pharmacologic activity. Transport of glycoside analogues across the channel is usually mediate by passive diffusion or active transporters (Na+-independent equilibrative transporters and Na+-dependent concentrative transporters). However, their chemical science properties square measure unsuitable for passive Transcellular viscous absorption. Meanwhile, glycoside analogues don't seem to be natural substrates and show low affinity for glycoside transporters. Hence, oral absorption of glycoside analogues is usually restricted [4].
Material and Methods
Carboxylicacidesters prodrugs
Carboxylicacidesters prodrug approach is wide wont to improve oral absorption of glycoside analogues, within which the group set at the aspect chain of glycoside analogues is esterified with organic acid and the other way around. The carboxylicacidesters-type prodrugs typically possess important improvement in water-solubility, semipermeable membrane porousness, protein stability and bioavailability, etc.
Acyclovir and its prodrugs
Acyclovir (ACV) belongs to BCS III category medication and possesses activity against human herpes viruses. However, as a result of its restricted bioavailability (20%), ACV shows moderate antiviral effectiveness when oral administration. Hence, it's necessary and possible to style a prodrug for rising oral absorption of ACV [5].
Valacyclovir (VACV) is that the essential amino acid organic compound prodrug of ACV targeting viscous oligopeptide transporter one (PepT1) and has been tried to be safe and effective drug. It’s been the foremost in prodrug targeting PepT1. PepT1 may be a protoncoupled transporting macromolecule and preponderantly distributed within the little viscous animal tissue cells. It became a placing prodrugdesigning target recently, since some poorly absorbed medication are often changed as peptidomimetic prodrugs targeting viscous PepT1 to enhance oral absorption of the parent drug. 3′-hydroxyl cluster of ACV was esterified with l-valine to arrange VACV. VACV has been reported to extend the oral bioavailability of ACV by 3- to 5-fold in humans [6].
After the eminent try of PepT1-targeted prodrug approach, the dipeptidylpeptidase IV (DPPIV/CD26) prodrug strategy was applied to ACV for improved water-solubility and oral bioavailability. DPPIV/CD26 belongs to a singular category of membrane-associated peptidases. It’s cosmopolitan on form of cell membranes, like numerous white cell subsets and several other styles of animal tissue, epithelium,and formative cell cells. What is more, a soluble sort of the protein has been detected in humour and plasma at low amounts [7].
Penciclovir and Famciclovir
Penciclovir is associate degree acyclic nucleoside glycoside analogues, that displays the same spectrum of property and antiviral activity compared with overtax .Due to its poor oral bioavailability. it's necessary to style AN oral different of penciclovir. Famciclovir could be a double prodrug containing ethanoyl radical diester and 6-deoxy promoieties. It is expeditiously bioactive to the parent drug via catalyst deacetylation and chemical reaction once oral administration. Famciclovir has been evidenced to be effective for human VD infections and herpes herpes zoster [8].Clinical studies incontestible the prodrug might be chop-chop absorbed and also the oral bioavailability of penciclovir rose up to seventy seven following one dose of famciclovir .In distinction, the ethanol radical diester of penciclovir didn't show any sweetening in oral absorption compared to the parent drug. Monocarbonate prodrug of 6-deoxy penciclovir was conjointly assessed in vivo with the hope of additional expeditiously changing the prodrug to the parent kind. Slightly higher or comparable urinary recovery of penciclovir was determined with many monocarbonate prodrugs in mice and rats compared to Famciclovir [9].
Conclusion
Nucleotide analogues play an important role within the treatment of cancer and viruses. Since the rate-limiting step within the formation of triphosphate is conversion of glycoside analogues to its monophosphate, monophosphate organic compound prodrugs of glycoside analogues were designed in an effort to bypass the initial phosphorylation activation step. However, each glycoside analogues and monophosphate organic compound prodrugs of glycoside analogues area unit polar molecules and have restricted membrane porosity. Hence, traverse of viscos animal tissue membrane is usually restricted. Over the past decade, many artistic prodrug methods are utilised to beat these limitations. The examples represented during this review illustrate the numerous analysis efforts done to enhance the oral bioavailability of glycoside analogues. Ancient prodrug approaches by enhancing lipophilicity are applied to enhance passive diffusion. Prodrugs targeted to PepT1 are found terribly helpful for enhancing oral absorption of polar medicine. PepT1 has become a promising target since they're extremely expressed within the bowel with high capability and numerous substrate specificity. Advances in prodrug style have improved the worth of glycoside compounds as metastatic tumor and antiviral agents. The example represented during this article any prove that prodrug approach is an efficient strategy for up oral absorption of glycoside analogues [10].
Acknowledgement
This work was financially supported from the Project for Science and Technology Plan of Liaoning Province.
References
- Rhie JK, Covitz KM, Smith PL, Lee CP, Oh DM, et al. ( 1998 ) 5'-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter. Pharm Res. 15: 1154-1159.
- Yao SY, Ng AM, Vickers MF, Sundaram M, Cass CE, et al. (2002) Functional and molecular characterization of nucleobase transport by recombinant human and rat equilibrative nucleoside transporters 1 and 2. Chimeric constructs reveal a role for the ENT2 helix 5-6 region in nucleobase translocation J Biol Chem 277: 24938-24948.
- Li F, Maag H, Alfredson T (2008) Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting. J Pharm Sci 7: 1109-34.
- Sinko PJ, Balimane PV (1998) Carrier-mediated intestinal absorption of valacyclovir, the L-valyl ester prodrug of acyclovir: 1. Interactions with peptides, organic anions and organic cations in rats. Bio pharm Drug Dispos 19: 209-217.
- Kong W, Engel K, Wang J (2004) Mammalian nucleoside transporters. Curr Drug Metab 5: 63-84.
- Chandrasena G, Giltay R, Patil SD, Bakken A, Unadkat JD, et al . (1997) Functional expression of human intestinal Na+-dependent and Na+-independent nucleoside transporters in Xenopus laevis oocytes. Biochem Pharmacol 53: 1909-1918.
- Marcal Pastor-Anglada, Pedro Cano-Soldado, Míriam Molina-Arcas, M Pillars Lostao, Ignacio Larráyoz, et al. (2005) Cell entry and export of nucleoside analogues. Virus Res 107: 151-64.
- Xin Lu, Shimei Gong, Anne Monks, Daniel Zaharevitz, Jeffrey A Moscow. (2002) Correlation of nucleoside and nucleobase transporter gene expression with antimetabolite drug cytotoxicity. J Exp Ther Oncol 2: 200-12.
- Toshiya Katsura, Ken-Ichi Inui (2003) Intestinal absorption of drugs mediated by drug transporters: mechanisms and regulation. Drug Metab Pharmacokinet 18: 1-15.
- O P Flint (1994) In vitro studies of the toxicity of nucleoside analogues used in the treatment of HIV infection. Toxicol In Vitro 8: 677-683.
Indexed at, Google Scholar, Crossref
Indexed at, Google Scholar, Crossref
Indexed at, Google Scholar, Crossref
Indexed at, Google Scholar, Crossref
Indexed at, Google Scholar, Crossref
Indexed at, Google Scholar, Crossref
Indexed at, Google Scholar, Crossref
Indexed at, Google Scholar, Crossref
Indexed at, Google Scholar, Crossref
Citation: Zang L (2022) Involvement of Multiple Transporters within the Oral Absorption of Glycoside Analogues. J Pharmacokinet Exp Ther 6: 146.
Copyright: © 2022 Zang L. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Share This Article
Open Access Journals
Article Usage
- Total views: 1258
- [From(publication date): 0-2022 - Nov 07, 2024]
- Breakdown by view type
- HTML page views: 1038
- PDF downloads: 220