The effects of pharmaceutical excipients on drug disposition

Buggins, Talia R.; Dickinson, Paul; Taylor, Glyn

doi:10.1016/j.addr.2007.08.017

Cited by 109 publications

(57 citation statements)

References 125 publications

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“…P-gp activity is modulated by the physical state of lipid bilayer where the protein actually resides. Several pharmaceutical agents of natural or synthetic origin that belong to various categories like the cosolvents, surfactants, polymer and lipid excipients were identified to have the P-gp inhibitory action (Buggins, Dickinson, Taylor, 2007). The mechanism of action differs with the type of excipient as presented in Table III (Bansal et al, 2009a).…”

Section: Pharmaceutical Excipientsmentioning

confidence: 99%

“…Excipients are safe, not absorbed from the intestine or gut and have wide pharmaceutical acceptance with a fair history of being incorporated into the parenteral and external formulations as solubilizing and stabilizing agents (Buggins, Dickinson, Taylor, 2007). Besides, in the present scenario, there is increasing development of novel drug delivery systems (DDS) like microspheres, nanoparticles and liposomes, all of which have inherent P-gp evading activity (Kim, Lim, 2002).…”

Section: Pharmaceutical Formulationsmentioning

confidence: 99%

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Overview of P-glycoprotein inhibitors: a rational outlook

Srivalli

Lakshmi

2012

Braz. J. Pharm. Sci.

186

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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Section: Pharmaceutical Excipientsmentioning

confidence: 99%

Section: Pharmaceutical Formulationsmentioning

confidence: 99%

Overview of P-glycoprotein inhibitors: a rational outlook

Srivalli

Lakshmi

2012

Braz. J. Pharm. Sci.

186

119

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“…(Lo, 2000; Wandel, Kim, Stein, 2013) Excipients are material used in drug formulations alongside the active compound. They were believed to be an inactive part of a drug formulation; however, studies demonstrated that excipients are not inert and they can have subtle effects on absorption or elimination of concomitant drugs administered (Buggins, Dickinson, Taylor, 2007). Many attempts have been made to evaluate the capability of excipients to augment drug BA.…”

mentioning

confidence: 99%

Effects of polyethylene glycols on intestinal efflux pump expression and activity in Caco-2 cells

Hodaei

Baradaran

Valizadeh

et al. 2015

Braz. J. Pharm. Sci.

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The present study was planned to investigate the influence of polyethylene glycols (PEGs) on the activity and expression of P-glycoprotein (P-gp). Sub-toxic concentrations of PEGs in Caco-2 cells were determined using the MTT test assay. Then the measurement of Rhodamine-123 (Rho-123) uptake, a P-gp fluorescence substrate, in Caco-2 cells confronting PEG 400 (1% and 2% w/v), PEG 4000 (2% and 4% w/v), PEG 6000 (2% and 4% w/v), PEG 10000 (2% and 4% w/v), PEG 15000 (1% and 2% w/v), and PEG 35000 (2% and 4% w/v) overnight was taken to elucidate whether non-toxic concentrations of PEGs are able to impact P-gp activity. Furthermore, western blotting was carried out to investigate P-gp protein expression. The results showed that PEG 400 at concentrations of 1% (w/v) and 2% (w/v) and PEG 6000 at the concentration of 4% (w/v) are notably capable of blocking P-gp. Based on the obtained results it is concluded that the mentioned excipients could be used to obstruct P-gp efflux transporter in order to increase the bioavailability of co-administered substrate drug.Uniterms: P-glycoprotein/activity. P-glycoprotein/expression. Caco-2. Rhodamine-123. Excipients. Drugs/bioavailability. Polyethylene glycol/effects. O presente estudo foi planejado para investigar a influência de polietileno glicóis sobre a atividade e expressão da P-glicoproteína (P-gp) . Concentrações sub-tóxicas de PGPs e em células Caco-2 foram determinadas por meio do ensaio de MTT. Em seguida, efetuou-se a a medida de captura de , um substrato fluorescente de P-gp, em células Caco-2, confrontando com PEG 400 (1% e 2% m/v), PEG 4000 (2% e 4% m/v) e PEG 6000 (2% e 4% m /v), PEG 10000 (2% e 4% w/v), PEG 15000 (1% e 2% m/v), e PEG 35000 (2% e 4% m/v). Essa medida foi efetuada durante a noite, para saber se as concentrações não tóxicas de excipientes são capazes de influenciar a actividade da P-gp. Além disso, realizou-se o western blotting para investigar a expressão da proteína P-gp. Os resultados mostraram que o PEG 400, nas concentrações de 1% (m/v) e 2% (m/v), e PEG 6000, na concentração de 4% (m/v) são capazes de bloquear P-gp. Com base nos resultados conclui-se que os excipientes mencionados poderiam ser utilizados para obstruir o efluxo por P-gp, a fim de aumentar a biodisponibilidade de do fármaco co-administrado.Unitermos: Glicoproteína-P/atividade. Glicoproteína-P/expressão. Caco-2. Rodamina-123. Excipientes. Fármacos/biodisponibilidade. Polietilenoglicol/efeitos. INTRODUCTIONWhile oral drug administration has many preferable characteristics, like intensified patient compliance and easier chronic administration as compared with other pharmaceutical forms, nearly 50% of orally taken drugs bioavailability (BA) is declined owing to their poor and inadequate absorption through intestinal mucosa (Gursoy, Benita, 2004; Shah et al., 2013).Membrane bound transport systems are one of the physiological factors that impact the intestinal absorption of drugs and therefore could be essential in drug pharmacokinetics and disposition alteration in the body. Among thes...

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“…In most cases, the formulation strategies require the use of various solvents and/or excipients during the production step. These excipients have to be approved or recognized as "generally recognized as safe" (GRAS) substances for pulmonary drug delivery [40,[44][45]. Moreover, the residual solvents have to be below some acceptable limits [46].…”

Section: Pulmonary Drug Deliverymentioning

confidence: 99%

Recent Developments in Inhaled Triazoles Against Invasive Pulmonary Aspergillosis

Merlos

Amighi

Wauthoz

2014

Curr Fungal Infect Rep

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Invasive pulmonary aspergillosis (IPA) presents high incidence and high mortality in immunocompromised patients. To combat or prevent IPA, triazoles such as voriconazole or itraconazole and posaconazole are becoming the first-or second-line therapy, respectively.However, triazoles present issues of oral bioavailability, high liver metabolism and/or drugdrug interactions, increasing the variability of systemic concentrations. To overcome these issues, inhalation is a promising route for delivering triazoles for prophylactic or curative therapy of IPA. Indeed, pulmonary drug delivery increases the drug in situ drastically while decreasing the systemic exposure, therefore limiting drug metabolisation, side effects and drug-drug interactions. Development of triazoles for inhalation has focused on voriconazole and itraconazole, drugs which are both highly permeable but present high solubility differences. In this review, the most complete and promising pharmaceutical developments for voriconazole and itraconazole are described.Keywords: aerosol, antifungal, aspergillosis, fungal infection, pulmonary delivery, dry powder inhaler, dry powder for inhalation, nebulizer, nebulization, cyclodextrin, nanoparticle, solid dispersion, controlled release drug delivery. Abbreviations: AI90H, amorphous itraconazole with Phospholipon

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The effects of pharmaceutical excipients on drug disposition

Cited by 109 publications

References 125 publications

Overview of P-glycoprotein inhibitors: a rational outlook

Overview of P-glycoprotein inhibitors: a rational outlook

Effects of polyethylene glycols on intestinal efflux pump expression and activity in Caco-2 cells

Recent Developments in Inhaled Triazoles Against Invasive Pulmonary Aspergillosis

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