Prodrugs

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Ashim K Mitra - One of the best experts on this subject based on the ideXlab platform.

  • peptide Prodrugs improved oral absorption of lopinavir a hiv protease inhibitor
    International Journal of Pharmaceutics, 2008
    Co-Authors: Sheetal Agarwal, Sai H.s. Boddu, Swapan K Samanta, Ritesh Jain, Ashim K Mitra
    Abstract:

    Abstract Lopinavir (LVR) is extensively metabolized by CYP3A4 and is prevented from entering the cells by membrane efflux pumps such as P-gp and MRP2. In an approach to evade the first-pass metabolism and efflux of LVR, peptide Prodrugs of LVR [valine–valine–lopinavir (VVL) and glycine–valine–lopinavir (GVL)] were synthesized. Prodrugs were identified with 1 H and 13 C NMR spectra and LC/MS/MS was employed to evaluate their mass and purity. Solubility studies indicated that the Prodrugs have enhanced aqueous solubilities relative to parent LVR. Accumulation and transport data of VVL and GVL across MDCKII-MDR1 and MDCKII-MRP2 cells indicated evasion of Prodrugs’ efflux by P-gp and MRP2 significantly. Permeability studies across Caco-2 cells indicated that the Prodrugs are transported by peptide transporters and have increased permeability as compared with LVR. VVL and GVL exhibited significantly better degradation rate constants as compared with LVR in rat liver microsomes. Enzymatic stability studies in Caco-2 cell homogenate indicated that the peptide Prodrugs are first converted to the ester intermediate (amino acid prodrug VL) and then finally to the parent drug. Overall, the advantages of utilizing peptide Prodrugs include chemical modification of the compound to achieve targeted delivery via peptide transporters present across the intestinal epithelium, significant evasion of efflux and CYP3A4 mediated metabolism and significantly better solubility profiles. Therefore, in vitro studies demonstrated that peptide prodrug derivatization of LVR may be an effective strategy for evading its efflux and enhancing its systemic concentrations.

  • transport of acyclovir ester Prodrugs through rabbit cornea and sirc rabbit corneal epithelial cell line
    Journal of Pharmaceutical Sciences, 2001
    Co-Authors: Ashim K Mitra
    Abstract:

    ABSTRACT The purpose of this study is to assess the permeability of acyclovir (ACV) Prodrugs through the rabbit corneal cell line (SIRC) as well as the cornea, and characterize the SIRC cell line for transport and metabolism studies of ester Prodrugs. Prodrug derivatization of an acycloguanosine antiviral agent, acyclovir, was employed to improve its permeability across the cornea. New Zealand albino rabbits were used as an animal model for corneal studies. The SIRC cell line grown on polyester membranes was used for transport of these Prodrugs. SIRC cells grown on the membrane support for 10 days developed four to six layers of epithelial cells, and this is comparable to the normal rabbit corneal epithelial layer. Transport experiments were conducted across the rabbit cornea and confluent SIRC cells using side‐by‐side diffusion‐cell apparatus. Enzymatic hydrolysis of these compounds was evaluated in SIRC cell lysates. Appropriate reversed phase HPLC method(s) were employed for quantitation of both the prodrug and ACV simultaneously. Corneal permeabilities of some of these Prodrugs (Malonyl ACV and Acetyl ACV) were higher relative to ACV. The SIRC cell line permeability values of all the Prodrugs were higher compared to that of the intact cornea. The total amount of ACV‐Prodrugs transported, i.e., unhydrolyzed Prodrugs and regenerated ACV, across the SIRC cell line was more relative to ACV. Hydrolytic studies in the SIRC cell line homogenate demonstrated the bioreversion potential of the Prodrugs and the presence of enzymes, particularly the cholinesterase in the SIRC cell line. It may be concluded that the SIRC cell line is leakier compared to the cornea. Keeping in mind the limitations, the SIRC cell line after further characterization may be used for transport and metabolism studies of ester Prodrugs. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1505–1515, 2001

  • transport of acyclovir ester Prodrugs through rabbit cornea and sirc rabbit corneal epithelial cell line
    Journal of Pharmaceutical Sciences, 2001
    Co-Authors: Rahul V Tak, Dhananjay Pal, Hongwu Gao, Surajit Dey, Ashim K Mitra
    Abstract:

    The purpose of this study is to assess the permeability of acyclovir (ACV) Prodrugs through the rabbit corneal cell line (SIRC) as well as the cornea, and characterize the SIRC cell line for transport and metabolism studies of ester Prodrugs. Prodrug derivatization of an acycloguanosine antiviral agent, acyclovir, was employed to improve its permeability across the cornea. New Zealand albino rabbits were used as an animal model for corneal studies. The SIRC cell line grown on polyester membranes was used for transport of these Prodrugs. SIRC cells grown on the membrane support for 10 days developed four to six layers of epithelial cells, and this is comparable to the normal rabbit corneal epithelial layer. Transport experiments were conducted across the rabbit cornea and confluent SIRC cells using side-by-side diffusion-cell apparatus. Enzymatic hydrolysis of these compounds was evaluated in SIRC cell lysates. Appropriate reversed phase HPLC method(s) were employed for quantitation of both the prodrug and ACV simultaneously. Corneal permeabilities of some of these Prodrugs (Malonyl ACV and Acetyl ACV) were higher relative to ACV. The SIRC cell line permeability values of all the Prodrugs were higher compared to that of the intact cornea. The total amount of ACV-Prodrugs transported, i.e., unhydrolyzed Prodrugs and regenerated ACV, across the SIRC cell line was more relative to ACV. Hydrolytic studies in the SIRC cell line homogenate demonstrated the bioreversion potential of the Prodrugs and the presence of enzymes, particularly the cholinesterase in the SIRC cell line. It may be concluded that the SIRC cell line is leakier compared to the cornea. Keeping in mind the limitations, the SIRC cell line after further characterization may be used for transport and metabolism studies of ester Prodrugs.

Gordon L. Amidon - One of the best experts on this subject based on the ideXlab platform.

  • the dipeptide monoester Prodrugs of floxuridine and gemcitabine feasibility of orally administrable nucleoside analogs
    Pharmaceuticals, 2014
    Co-Authors: Yasuhiro Tsume, Blanca Borras Bermejo, Gordon L. Amidon
    Abstract:

    Dipeptide monoester Prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester Prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine Prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide Prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.

  • The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs
    MDPI AG, 2014
    Co-Authors: Yasuhiro Tsume, Blanca Borras Bermejo, Gordon L. Amidon
    Abstract:

    Dipeptide monoester Prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester Prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine Prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide Prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents

  • the feasibility of enzyme targeted activation for amino acid dipeptide monoester Prodrugs of floxuridine cathepsin d as a potential targeted enzyme
    Molecules, 2012
    Co-Authors: Yasuhiro Tsume, Gordon L. Amidon
    Abstract:

    The improvement of therapeutic efficacy for cancer agents has been a big challenge which includes the increase of tumor selectivity and the reduction of adverse effects at non-tumor sites. In order to achieve those goals, prodrug approaches have been extensively investigated. In this report, the potential activation enzymes for 5¢-amino acid/dipeptide monoester floxuridine Prodrugs in pancreatic cancer cells were selected and the feasibility of enzyme specific activation of Prodrugs was evaluated. All Prodrugs exhibited the range of 3.0–105.7 min of half life in Capan-2 cell homogenate with the presence and the absence of selective enzyme inhibitors. 5¢-O-L-Phenylalanyl-L-tyrosyl-floxuridine exhibited longer half life only with the presence of pepstatin A. Human cathepsin B and D selectively hydrolized 5¢-O-L-phenylalanyl-L-tyrosylfloxuridine and 5¢-O-L-phenylalanyl-L-glycylfloxuridine compared to the other tested Prodrugs. The wide range of growth inhibitory effect by floxuridine Prodrugs in Capan-2 cells was observed due to the different affinities of prodrug promoieties to enyzmes. In conclusion, it is feasible to design Prodrugs which are activated by specific enzymes. Cathepsin D might be a good candidate as a target enzyme for prodrug activation and 5¢-O-L-phenylalanyl-L-tyrosylfloxuridine may be the best candidate among the tested floxuridine Prodrugs.

  • The Feasibility of Enzyme Targeted Activation for Amino Acid/Dipeptide Monoester Prodrugs of Floxuridine; Cathepsin D as a Potential Targeted Enzyme
    MDPI AG, 2012
    Co-Authors: Gordon L. Amidon, Yasuhiro Tsume
    Abstract:

    The improvement of therapeutic efficacy for cancer agents has been a big challenge which includes the increase of tumor selectivity and the reduction of adverse effects at non-tumor sites. In order to achieve those goals, prodrug approaches have been extensively investigated. In this report, the potential activation enzymes for 5¢-amino acid/dipeptide monoester floxuridine Prodrugs in pancreatic cancer cells were selected and the feasibility of enzyme specific activation of Prodrugs was evaluated. All Prodrugs exhibited the range of 3.0–105.7 min of half life in Capan-2 cell homogenate with the presence and the absence of selective enzyme inhibitors. 5¢-O-L-Phenylalanyl-L-tyrosyl-floxuridine exhibited longer half life only with the presence of pepstatin A. Human cathepsin B and D selectively hydrolized 5¢-O-L-phenylalanyl-L-tyrosylfloxuridine and 5¢-O-L-phenylalanyl-L-glycylfloxuridine compared to the other tested Prodrugs. The wide range of growth inhibitory effect by floxuridine Prodrugs in Capan-2 cells was observed due to the different affinities of prodrug promoieties to enyzmes. In conclusion, it is feasible to design Prodrugs which are activated by specific enzymes. Cathepsin D might be a good candidate as a target enzyme for prodrug activation and 5¢-O-L-phenylalanyl-L-tyrosylfloxuridine may be the best candidate among the tested floxuridine Prodrugs

  • amino acid ester Prodrugs of 2 bromo 5 6 dichloro 1 β d ribofuranosyl benzimidazole enhance metabolic stability in vitro and in vivo
    Journal of Pharmacology and Experimental Therapeutics, 2005
    Co-Authors: Philip L. Lorenzi, Christopher P. Landowski, John M. Hilfinger, Xueqin Song, John C Drach, Leroy B Townsend, Katherine Z Borysko, Julie M Breitenbach, Jae Seung Kim, Gordon L. Amidon
    Abstract:

    2-Bromo-5,6-dichloro-1-(beta-d-ribofuranosyl)benzimidazole (BDCRB) is a potent and selective inhibitor of human cytomegalovirus (HCMV), but it lacks clinical utility due to rapid in vivo metabolism. We hypothesized that amino acid ester Prodrugs of BDCRB may enhance both in vitro potency and systemic exposure of BDCRB through evasion of BDCRB-metabolizing enzymes. To this end, eight different amino acid Prodrugs of BDCRB were tested for N-glycosidic bond stability, ester bond stability, Caco-2 cell uptake, antiviral activity, and cytotoxicity. The Prodrugs were resistant to metabolism by BDCRB-metabolizing enzymes, and ester bond cleavage was rate-limiting in metabolite formation from prodrug. Thus, BDCRB metabolism could be controlled by the selection of promoiety. In HCMV plaque-formation assays, l-Asp-BDCRB exhibited 3-fold greater selectivity than BDCRB for inhibition of HCMV replication. This potent and selective antiviral activity in addition to favorable stability profile made l-Asp-BDCRB an excellent candidate for in vivo assessment and pharmacokinetic comparison with BDCRB. In addition to rapid absorption and sufficient prodrug activation after oral administration to mice, l-Asp-BDCRB exhibited a 5-fold greater half-life than BDCRB. Furthermore, the sum of area under the concentration-time profile (AUC)(BDCRB) and AUC(prodrug) after l-Asp-BDCRB administration was roughly 3-fold greater than AUC(BDCRB) after BDCRB administration, suggesting that a reservoir of prodrug was delivered in addition to parent drug. Overall, these findings demonstrate that amino acid Prodrugs of BDCRB exhibit evasion of metabolizing enzymes (i.e., bioevasion) in vitro and provide a modular approach for translating this in vitro stability into enhanced in vivo delivery of BDCRB.

David F Ackerley - One of the best experts on this subject based on the ideXlab platform.

  • evaluating the abilities of diverse nitroaromatic prodrug metabolites to exit a model gram negative vector for bacterial directed enzyme prodrug therapy
    Biochemical Pharmacology, 2018
    Co-Authors: Jasmine V E Chanhyams, Janine N Copp, Jeff B Smaill, Adam V Patterson, David F Ackerley
    Abstract:

    Gene-directed enzyme-prodrug therapy (GDEPT) employs tumour-tropic vectors including viruses and bacteria to deliver a genetically-encoded prodrug-converting enzyme to the tumour environment, thereby sensitising the tumour to the prodrug. Nitroreductases, able to activate a range of promising nitroaromatic Prodrugs to genotoxic metabolites, are of great interest for GDEPT. The bystander effect (cell-to-cell transfer of activated prodrug metabolites) has been quantified for some nitroaromatic Prodrugs in mixed multilayer human cell cultures, however while these provide a good model for viral DEPT (VDEPT) they do not inform on the ability of these prodrug metabolites to exit bacterial vectors (relevant to bacterial-DEPT (BDEPT)). To investigate this we grew two Escherichia coli strains in co-culture; an activator strain expressing the nitroreductase E. coli NfsA and a recipient strain containing an SOS-GFP DNA damage responsive gene construct. In this system, induction of GFP by reduced prodrug metabolites can only occur following their transfer from the activator to the recipient cells. We used this to investigate five clinically relevant Prodrugs: metronidazole, CB1954, nitro-CBI-DEI, and two dinitrobenzamide mustard prodrug analogues, PR-104A and SN27686. Consistent with the bystander efficiencies previously measured in human cell multilayers, reduced metronidazole exhibited little bacterial cell-to-cell transfer, whereas nitro-CBI-DEI was passed very efficiently from activator to recipient cells post-reduction. However, in contrast with observations in human cell multilayers, the nitrogen mustard prodrug metabolites were not effectively passed between the two bacterial strains, whereas reduced CB1954 was transferred efficiently. Using nitroreductase enzymes that exhibit different biases for the 2- versus 4-nitro substituents of CB1954, we further showed that the 2-nitro reduction products exhibit substantially higher levels of bacterial cell-to-cell transfer than the 4-nitro reduction products, consistent with their relative bystander efficiencies in human cell culture. Overall, our data suggest that Prodrugs may differ in their suitability for VDEPT versus BDEPT applications and emphasise the importance of evaluating an enzyme-prodrug partnership in an appropriate context for the intended vector.

  • the flavin reductase msue is a novel nitroreductase that can efficiently activate two promising next generation Prodrugs for gene directed enzyme prodrug therapy
    Cancers, 2013
    Co-Authors: Laura K Green, Janine N Copp, Jeff B Smaill, Adam V Patterson, Mathew A Storey, Elsie M Williams, David F Ackerley
    Abstract:

    Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of Prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy (GDEPT). Two promising hypoxia Prodrugs for GDEPT are the dinitrobenzamide mustard PR-104A, and the nitrochloromethylbenzindoline prodrug nitro-CBI-DEI. We describe here use of a nitro-quenched fluorogenic probe to identify MsuE from Pseudomonas aeruginosa as a novel nitroreductase candidate for GDEPT. In SOS and bacteria-delivered enzyme prodrug cytotoxicity assays MsuE was less effective at activating CB1954 (a first-generation GDEPT prodrug) than the “gold standard” nitroreductases NfsA and NfsB from Escherichia coli. However, MsuE exhibited comparable levels of activity with PR-104A and nitro-CBI-DEI, and is the first nitroreductase outside of the NfsA and NfsB enzyme families to do so. These in vitro findings suggest that MsuE is worthy of further evaluation in in vivo models of GDEPT.

Ingrid Schuberth - One of the best experts on this subject based on the ideXlab platform.

Caroline J. Springer - One of the best experts on this subject based on the ideXlab platform.

  • attenuated salmonella targets prodrug activating enzyme carboxypeptidase g2 to mouse melanoma and human breast and colon carcinomas for effective suicide gene therapy
    Clinical Cancer Research, 2008
    Co-Authors: Frank Friedlos, Lawrence Davies, Richard Marais, Jan Martin, Douglas Hedley, Lesley Ogilvie, Ivan King, David Bermudes, Panos Lehouritis, Caroline J. Springer
    Abstract:

    PURPOSE: We engineered the oncolytic Salmonella typhimurium-derived bacterium VNP20009 as a vector to target delivery to tumors of the prodrug-activating enzyme carboxypeptidase G2 (CPG2) and to show enhanced antitumor efficacy on administration of different Prodrugs. EXPERIMENTAL DESIGN: We characterized CPG2 expression in vectors by immunoblotting, immunofluorescence, and enzyme activity. We assessed prodrug activation by high-performance liquid chromatography. Target human tumor cell and bacterial vector cell cytotoxicity was measured by flow cytometry and colony-forming assays. Therapy was shown in two human tumor xenografts and one mouse allograft with postmortem analysis of bacterial and CPG2 concentration in the tumors. RESULTS: CPG2 is expressed within the bacterial periplasm. It activates Prodrugs and induces cytotoxicity in human tumor cells but not in host bacteria. Following systemic administration, bacteria multiply within xenografts reaching 2 x 10(7)/g to 2 x 10(8)/g at 40 days postinoculation. The concentration of CPG2 in these tumors increases steadily to therapeutic levels of 1 to 6 units/g. The bacteria alone reduce the growth of the tumors. Subsequent administration of Prodrugs further reduces significantly the growth of the xenografts. CONCLUSIONS: The bacteria multiply within tumors, resulting in a selective expression of CPG2. The CPG2-expressing bacteria alone reduce the growth of tumors. However, in the presence of Prodrugs activated by CPG2, this oncolytic effect is greatly increased. We conclude that bacterial oncolytic therapy, combined with CPG2-mediated prodrug activation, has great potential in the treatment of a range of cancers.

  • novel fluorinated Prodrugs for activation by carboxypeptidase g2 showing good in vivo antitumor activity in gene directed enzyme prodrug therapy
    Journal of Medicinal Chemistry, 2005
    Co-Authors: Lawrence Davies, Frank Friedlos, Jan Martin, Douglas Hedley, Lesley Ogilvie, Ian Scanlon, Caroline J. Springer
    Abstract:

    Sixteen novel polyfluorinated benzoic acid mustards have been synthesized for use in gene-directed enzyme prodrug therapy (GDEPT). Eight of these were benzoic acid l-glutamate mustards for evaluation as Prodrugs and the other eight were the active drugs formed by the action of the bacterial enzyme carboxypeptidase G2 (CPG2). All of the di- and trifluorinated Prodrugs were efficiently cleaved by the enzyme. In contrast, the tetrafluorinated Prodrugs were found to be competitive inhibitors of CPG2, the first such inhibitors to have been described. The di- and trifluorinated Prodrugs were differentially cytotoxic to human breast carcinoma cells (MDA MB 361) expressing CPG2, compared to control cells that did not express the enzyme. The difluorinated prodrug {4-[bis(2-bromoethyl)amino]-3,5-difluorobenzoyl}-l-glutamic acid and its iodoethylamino analogue were effective substrates for the enzyme and showed excellent therapeutic activity in CPG2-expressing MDA MB 361 xenografts, either curing or greatly inhibiti...

  • three new Prodrugs for suicide gene therapy using carboxypeptidase g2 elicit bystander efficacy in two xenograft models
    Cancer Research, 2002
    Co-Authors: Frank Friedlos, Janet L Martin, Lawrence Davies, Robert A Spooner, Richard Marais, Ion Niculescuduvaz, Lesley Ogilvie, Ian Scanlon, Stephen M Stribbling, Caroline J. Springer
    Abstract:

    ABSTRACT Three new Prodrugs, {prodrug 1: 4-[bis(2-iodoethyl)amino]-phenyloxy-carbonyl- L -glutamic acid; prodrug 2: 3-fluoro-4-[bis(2-chlorethyl)amino]-benzoyl- L -glutamic acid; and prodrug 3: 3,5-difluoro-4-[bis(2-iodoethyl)-amino]benzoyl- L -glutamic acid} have been assessed for use with amutant of carboxypeptidase G2 (CPG2, glutamate carboxypeptidase, EC3.4.17.11,) engineered to be tethered to the outer tumor cell surface(stCPG2(Q)3) as the activating enzyme in suicide gene therapy systems.All three of the Prodrugs produce much greater cytotoxicity differentialsbetween stCPG2(Q)3- and control -galactosidase ( -gal)-expressingbreast carcinoma MDA MB 361 and colon carcinoma WiDr cells (70- to450-fold) than was previously observed (19- to 27-fold) with 4-[(2-chloro-ethyl)(2-mesyloxyethyl)amino]benzoyl- L -glutamic acid (CMDA). Prodrug1 is the most effective antitumor agent in xenografts in mice inoculatedwith 100% stCPG2(Q)3-expressing MDA MB 361 cells, whereas Prodrugs2 and 3 are most effective when the percentage of stCPG2(Q)3-expressingcells is 50% or 10%. In nude mice bearing xenografts arising from inoculaof 100% stCPG2(Q)3-expressing WiDr cells, prodrug 2 is the most effec-tive antitumor agent. All three of the Prodrugs produced histologicalevidence of substantial bystander cell killing in WiDr xenografts in whichonly 10% or 50% of the cells inoculated were expressing stCPG2(Q)3. Weconclude that all three of the Prodrugs are more effective therapeuticallywith stCPG2(Q)3 than is the previously described prodrug CMDA and,also, that the optimal choice of prodrug varies among different tumortypes and that Prodrugs, optimized for their bystander effect, are effectivewhen only low percentages of cells in a tumor express CPG2.

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