PHARMACOKINETICS, PHARMACODYNAMICS AND DRUG METABOLISMSpecies Differences of Inhibitory Effects on P‐glycoprotein‐mediateD Drug Transport
Section snippets
INTRODUCTION
P‐glycoprotein (P‐gp) encoded by multidrug resistance 1 (MDR1) was found to be an energy‐dependent efflux transporter driven by ATP hydrolysis in Chinese hamster ovary cell mutants.1., 2., 3. P‐gp is localized in the apical membrane of cells4 and can transport a variety of compounds including drugs. Since P‐gp exhibits broad substrate specificity, P‐gp expressing cells show cross‐resistance to diverse drugs. In addition, since P‐gp is expressed not only in tumor cells but in normal tissue such
Materials
[3H]Daunorubicin (303.4 or 592.0 GBq/mmol) and [3H]digoxin (358.4 GBq/mmol) were purchased from PerkinElmer Life Sciences (Boston, MA). [mebmt‐β‐3H]Cyclosporin A (296.0 GBq/mmol) was obtained from Amersham Biosciences (Buckinghamshire, UK). Colchicine, quinidine sulfate dihydrate, and verapamil hydrochloride were purchased from Wako Pure Chemical Industries (Osaka, Japan). All other materials were of the highest purity available.
Cell Culture
The MDR1 transfected cell lines designated as hMDR1 (human MDR1),
Effect of Quinidine and Verapamil on P‐gp‐Mediated Drug Transport in MDR1 Transfected Cells and Mock Cells
The transcellular transports of daunorubicin in the presence of quinidine and verapamil, which are known as P‐gp inhibitors, are shown in Figures 1 and 2. In the MDR1 transfected cells, the basolateral‐to‐apical transport of daunorubicin was decreased, while the apical‐to‐basolateral transport was increased by quinidine and verapamil in a concentration‐dependent manner. On the other hand, in the mock cells, the transcellular transport of daunorubicin did not change in the presence of inhibitors.
DISCUSSION
It is increasingly recognized that drug transporters as well as drug metabolizing enzymes also play important roles in drug absorption, distribution, and excretion. The functions of the transporter proteins have been characterized by in vitro and in vivo experiments using tumor cells, transporter protein overexpressing cells, or gene‐knockout animals.8 The efflux drug transporter P‐gp is the best studied among ATP‐binding cassette drug efflux transporters to date. P‐gp was clarified to play key
Acknowledgements
We acknowledge Mr. Brent Bell for reviewing the manuscript.
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2024, Journal of Pharmaceutical SciencesFreshly isolated retinal capillaries to determine efflux transporter function at the inner BRB
2022, Journal of Controlled ReleaseCitation Excerpt :As shown in Fig. 2b, in the control group, NBD-cyclosporin A uptake reached 88.2 ± 3.4 μL/mg protein (n = 8) after 60 min. In the presence of the competitive P-gp substrates [29] verapamil (100 μM) and quinidine (100 μM), NBD-cyclosporin A uptake was increased 1.7-fold and 1.4-fold compared to the control, respectively. In contrast, probenecid and p-aminohippurate (PAH) had no statistically significant effect on NBD-cyclosporin A uptake.
The road (not) taken – Placental transfer and interspecies differences; The road not taken
2021, PlacentaCitation Excerpt :Organic anion transporter 4 (OAT4) orthologues have not been detected in mice and rats. Differences in amino acid sequences can influence transport efficiency but also inhibitory effects of other substances, as demonstrated for P-glycoprotein (P-gp) in terms of cyclosporin A and others [34,35]. While in humans and mice P-gp expression declines with progression of pregnancy, it is reported to increase in rats.
Interspecies comparison of putative ligand binding sites of human, rat and mouse P-glycoprotein
2018, European Journal of Pharmaceutical SciencesCitation Excerpt :This would require a comprehensive comparison of the putative binding sites of the P-gp structures across species. Literature sheds little light on this, suggesting the need for exploration of species-related differences in P-gp mediated drug transport activity (Martignoni et al., 2006; Schwab et al., 2003; Suzuyama et al., 2007). Inhibition of P-gp activity as a result of drug interactions has been reported in both animals and humans (Bussey, 1982; Choo et al., 2000; Pedersen, 1985), but only a few studies discussed species-related differences in the inhibitory effects on the P-gp function (Chu et al., 2013; Suzuyama et al., 2007; Zolnerciks et al., 2011).
Rat precision-cut intestinal slices to study P-gp activity and the potency of its inhibitors ex vivo
2015, Toxicology in VitroCitation Excerpt :In the present study, the rank order of the IC50 values of the used inhibitors agreed very well with published data on the Ki of these compounds for rat P-gp. Compared with human cell data, we found a difference in the rank order of verapamil and quinidine, which is probably due to a species difference, which is in line with the data of Suzuyama et al. who found different relative IC50 values for different animal species using quinidine and verapamil as P-gp inhibitors (Suzuyama et al., 2007). Since the PCIS technique can be applied to human intestine as well (de Graaf et al., 2010; van de Kerkhof et al., 2008), it will be very interesting to study the inhibitory potency of inhibitors in human PCIS prepared from human intestine.
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