Circumventing P-Glycoprotein-Mediated Cellular Efflux of Quinidine by Prodrug Derivatization

Jain, Ritesh; Majumdar, Soumyajit; Nashed, Yasser E.; Pal, Dhananjay; Mitra, Ashim K.

doi:10.1021/mp049952s

Cited by 40 publications

(24 citation statements)

References 35 publications

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“…This result indicated that DP is highly susceptible to alkaline hydrolysis relative to acidic hydrolysis. Similar results have been observed for a wide range of amino acid prodrugs developed previously in our laboratory (35,36,39,40). Lower degradation half-life at pH 7.4 suggests that a large amount of DP may degrade in precorneal tear fluid upon topical administration to regenerate prednisolone.…”

Section: Buffer Stability Studiessupporting

confidence: 86%

Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation

2015

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Abstract. A series of stereoisomeric prodrugs have been designed to examine efficacy in generating higher corneal absorption relative to prednisolone. Prodrugs have been studied and identified with LC/MS/MS and NMR analyses. Prodrugs have been characterized for aqueous solubility, buffer stability, and cytotoxicity. Cellular uptake and permeability studies have been conducted across MDCK-MDR1 cells to determine prodrug affinity towards P-glycoprotein (P-gp) and peptide transporters. Enzyme-mediated degradation of prodrugs has been determined using Statens Seruminstitut rabbit cornea (SIRC) cell homogenates. Prodrugs exhibited higher aqueous solubility relative to prednisolone. Prodrugs circumvented P-gp-mediated cellular efflux and were recognized by peptide transporters. Prodrugs (DP, DDP) produced with D-isomers (D-valine) were significantly stable against both chemical and enzymatic hydrolyses. The order of degradation rate constants observed in chemical and enzymatic hydrolyses were in the same order, i.e., L-valine-L-valine-prednisolone (LLP)>L-valine-D-valine-prednisolone (LDP)>D-valine-L-valine-prednisolone (DLP)>D-valine-D-valine-prednisolone (DDP). Results obtained from this study clearly suggest that stereoisomeric prodrug approach is an effective strategy to overcome P-gpmediated efflux and improve transcorneal permeability of prednisolone following topical administration.

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Section: Buffer Stability Studiessupporting

confidence: 86%

Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation

2015

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“…In a drug discovery process, prodrugs are often designed to improve the pharmacological and pharmacokinetic properties of the drugs. Val-quinidine, a prodrug obtained by derivatization of quinidine was reported successful in circumventing P-gp transport (Jain et al, 2004). The first and third generation PAMAM dendrimer based prodrugs showed potency as membrane permeability enhancing P-gp inhibitors for P-gp substrate drugs (Thiagarajan et al, 2010).…”

Section: Pharmaceutical Prodrugsmentioning

confidence: 99%

Overview of P-glycoprotein inhibitors: a rational outlook

Srivalli

Lakshmi

2012

Braz. J. Pharm. Sci.

189

119

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P-glycoprotein (P-gp), a transmembrane permeability glycoprotein, is a member of ATP binding cassette (ABC) super family that functions specifically as a carrier mediated primary active efflux transporter. It is widely distributed throughout the body and has a diverse range of substrates. Several vital therapeutic agents are substrates to P-gp and their bioavailability is lowered or a resistance is induced because of the protein efflux. Hence P-gp inhibitors were explored for overcoming multidrug resistance and poor bioavailability problems of the therapeutic P-gp substrates. The sensitivity of drug moieties to P-gp and vice versa can be established by various experimental models in silico, in vitro and in vivo. Ever since the discovery of P-gp, the research plethora identified several chemical structures as P-gp inhibitors. The aim of this review was to emphasize on the discovery and development of newer, inert, non-toxic, and more efficient, specifically targeting P-gp inhibitors, like those among the natural herb extracts, pharmaceutical excipients and formulations, and other rational drug moieties. The applications of cellular and molecular biology knowledge, in silico designed structural databases, molecular modeling studies and quantitative structure-activity relationship (QSAR) analyses in the development of novel rational P-gp inhibitors have also been mentioned. Glicoproteína-p (P-gp), uma glicoproteína de transmembrana permeável, é um membro da superfamília (ABC) de cassete de gene de ligação de ATP que funciona especificamente como um carreador mediado pelo transportador de efluxo ativo primário. É amplamente distribuído por todo o corpo e apresenta uma gama diversificada de substratos. Diversos agentes terapêuticos vitais são substratos para P-gp e sua biodisponibilidade é reduzida ou a resistência é induzida devido ao efluxo de proteínas. Portanto, os inibidores da P-gp foram explorados para a superação da resistência a múltiplas drogas e problemas de biodisponibilidade deficiente dos substratos terapêuticos da P-gp. A sensibilidade das moléculas da droga à P-gp e vice-versa, pode ser estabelecida por vários modelos experimentais in silico, in vitro e in vivo. Desde a descoberta da P-gp, diversas pesquisas identificaram várias estruturas químicas como inibidores da P-gp. O objetivo deste presente estudo foi o de enfatizar a descoberta e desenvolvimento de inibidores mais novos, inertes, atóxicos e mais eficazes, visando especificamente os da P-gp, como aqueles entre os extratos vegetais, excipientes e formulações farmacêuticas, e outras moléculas racionais de droga. As aplicações do conhecimento de biologia celular e molecular, bancos de dados estruturais in silico, estudos de modelagem molecular e análises da relação quantitativa estrutura-atividade (QSAR) no desenvolvimento de novos inibidores racionais da P-gp também foram mencionados.Unitermos: Glicoproteína-p. Resistência a múltiplas drogas. Cluster de diferenciação 243. Esfingolipídeos. Inibidores competitivos.

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“…We have recently reported from our laboratory that peptide prodrug modification of compounds that are P-gp substrates resulted in partial evasion of P-gp mediated efflux (Jain et al, 2004;Jain et al, 2005). Following this discovery, we have used MDCKII-MDR1 cell line for studying peptide-mediated drug influx of peptide prodrug derivatives of compounds which were originally P-gp substrates.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of peptide transporters in MDCKII–MDR1 cell line as a model for oral absorption studies

Agarwal

Jain

Pal

et al. 2007

International Journal of Pharmaceutics

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MDCKII-MDR1 cell line has been extensively selected as a model to study P-gp-mediated drug efflux. Recently, investigators have employed this cell line for studying influx of peptide prodrug derivatives of parent compounds which are P-gp substrates. Therefore, the objective of this study is to functionally characterize the peptide mediated uptake and transport of [ 3 H] Glycylsarcosine ([ 3 H] Gly-Sar), a model peptide substrate across MDCKII-MDR1 cells. [ 3 H] Gly-Sar uptake from apical (AP) and basolateral (BL) membranes was found to be time dependent and saturable. MichaelisMenten (Km) constants of [ 3 H] Gly-Sar uptake across the AP and BL directions in MDCKII-MDR1 cell line were found to be 457 ± 37 μM and 464 ± 85 μM respectively. Vmax values in AP and BL directions for the peptide transporters in MDCKII-MDR1 cell line were calculated to be 0.035 ± 0.001 and 0.35 ± 0.034 pmol/min/mg protein respectively. Uptake of [ 3 H] Gly-Sar was significantly inhibited in the presence of aminocephalosporins and ACE-Inhibitors, known substrates for peptide transporters in both the AP and BL directions. Permeability of [ 3 H] Gly-Sar in the BL direction was maximal at pH 4 as compared to pH 5, 6 and 7.4 whereas such permeability in the AP direction was optimal at pH 7.4. Transepithelial transport of [ 3 H] Gly-Sar in the AP-BL direction was significantly lower than from BL-AP direction at all observed pHs. No statistical difference was observed in the transepithelial permeability of [ 3 H] Gly-Sar across both AP and BL directions over 4-10 days of growth period. The present study indicates that peptide transporters are effectively involved in the bidirectional transport of Gly-Sar across MDCKII-MDR1 cell line; the BL peptide transporter can transport Gly-Sar at a greater rate as compared to the AP peptide transporter. Results from these studies suggest the application of MDCKII-MDR1 cell line as a rapid effective tool to study peptide mediated influx of compounds that may be substrates for both P-gp and peptide transporters.

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Circumventing P-Glycoprotein-Mediated Cellular Efflux of Quinidine by Prodrug Derivatization

Cited by 40 publications

References 35 publications

Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation

Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation

Overview of P-glycoprotein inhibitors: a rational outlook

Functional characterization of peptide transporters in MDCKII–MDR1 cell line as a model for oral absorption studies

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