0000000000249484
AUTHOR
Hilde Spahn-langguth
Modulation of drug transport by selected flavonoids: Involvement of P-gp and OCT?
Flavonoids, as a common component of daily nutrition, are a possible source of interference with absorption processes, due to modulation of transporting proteins. In this study, the influence of selected flavonoids (quercetin, isoquercitrin, spiraeoside, rutin, kaempferol, naringenin, naringin, and kaempferol) on the transport of the P-gp substrate [3H]talinolol across Caco-2 cell monolayers was investigated. To elucidate the mechanism behind the interaction observed in this system the potency of the flavonoids to replace [3H]talinolol from its P-gp binding site as well as their activity to inhibit OCT2-mediated [14C]TEA uptake into LLC-PK(1) cells were measured, as P-gp and OCT have been s…
Nanosuspension Formulations for Low-Soluble Drugs: Pharmacokinetic Evaluation Using Spironolactone as Model Compound
Various particle sizes of spironolactone as a model low solubility drug were formulated to yield micro-and nanosuspensions of the type solid lipid nanoparticles and DissoCubes. Seven oral and one i.v. formulations were tested in an in vivo pharmacokinetic study in rats with the aim of characterizing the bioavailability of spironolactone on the basis of its metabolites canrenone and 7-alpha-thiomethylspirolactone. In addition, a dose escalation study was carried out using nonmicronized spironolactone suspension as well as a nanosuspension type DissoCubes. On the basis of AUC as well as Cmax ratios, three groups of formulations were distinguished. The biggest improvement was seen with a solid…
Pharmacokinetic evaluation of oral fenofibrate nanosuspensions and SLN in comparison to conventional suspensions of micronized drug.
An increasing number of newly developed drugs show bioavailability problems due to poor water solubility. Formulating the drugs as nanosuspensions may help to overcome these problems by increasing saturation solubility and dissolution velocity. In the present study the bioavailability of the poorly soluble fenofibrate following oral administration was investigated in rats. Four formulations were tested: a nanosuspension type DissoCube(R), one solid lipid nanoparticle (SLN) preparation and two suspensions of micronized fenofibrate as reference formulations, one suspension in sirupus simplex and a second in a solution of hydroxyethy-cellulose in physiological saline. Both colloidal drug deliv…
Selective downregulation of the MDR1 gene product in Caco-2 cells by stable transfection to prove its relevance in secretory drug transport.
Considerable interest is focused on overcoming multidrug resistance (MDR) in cancer chemotherapy. The in vitro experiments to characterize P-glycoprotein's (P-gp) function and to decrease its effects have led to a variety of strategies such as addition of competitors or supplementation of the medium with oligonucleotides complementary to the 5'-end of the MDR1-mRNA. For the Caco-2 cell line, an in vitro model for absorption screening, expressing multiple transporters including P-gp, which pumps substances back into the apical solution, P-gp activity might mask other relevant transport proteins' activity. The objective of the present study was to construct a Caco-2 subline with reduced P-gp …
Bidirectional membrane transport: Simulations of transport inhibition in uptake studies explain data obtained with flavonoids
The purpose of the simulations was to obtain an estimate of concentration-dependent uptake curves when two counteracting transporters are present. On the basis of this experimental data obtained with a pair of ovarian carcinoma cell lines, one of which was not expressing the exsorptive transporter P-glycoprotein and one of which was an MDR1-transfected, P-glycoprotein expressing variant, the kinetics of cellular uptake of the radiolabel (3)H-talinolol were calculated and the inhibitory constants at P-gp were determined for different flavonoids. With respect to the inhibition of P-gp function, among others, naringenin and isoquercitrin were identified as inhibitors, yet estimation of the inh…