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• W2914219655 abstract "Pharmacokinetic studies in horses often demonstrate large interindividual differences. Such differences in the plasma concentrations of drugs can be caused by different expression levels or altered activity of metabolic enzymes and transporter proteins in blood-tissue barriers or in excretory organs. The MDR-1 (Multidrug resistance) gene codes for the P-glycoprotein (P-gp). This efflux transporter can limit the oral absorption of drugs, promote their elimination in bile and urine and prevent their accumulation in the central nervous system. The aim of this study was to examine if the MDR-1 gene expression allows for the prediction of the pharmacokinetic behaviour of the P-gp substrate ivermectin. Since access to important organs, such as the liver and intestine, is restricted, the correlation between the MDR-1 gene expression in the liver and an easily accessible tissue was examined. Due to their accessibility and expression of the MDR-1 gene, hair follicle cells were chosen. However no significant correlation between the MDR-1 gene expression in hair follicle cells and the liver could be demonstrated (rs= 0.41; r²= 0.70). Nonetheless, a simultaneously high MDR-1 gene expression in the liver and in hair follicle cells could be seen. Marked differences in the MDR-1 gene expression in hair follicle cells of a large number of horses (n= 49) were measured. A pharmacokinetic study was carried out with the six horses demonstrating the highest and with the five horses exhibiting the lowest MDR-1 gene expression. No significant differences could be determined for the plasma concentration vs. time profiles, as well as for the other pharmacokinetic parameters of Ivermectin between horses with different MDR-1 gene expression. However, the two horses with the highest MDR-1 gene expression demonstrated lower ivermectin concentrations at all sample time points. Accordingly, the maximal plasma concentration and the area under the curve of Ivermectin for these two horses were lower while the Ivermectin clearance was markedly higher than for the other horses. No differences were seen in the terminal phase disposition rate and the half-life of the terminal phase. The relationship between the MDR-1 gene expression in hair follicle cells and the pharmacokinetic behaviour does not seem to be very straightforward. Whilst altered pharmacokinetics could be observed for the two horses with the highest MDR-1 gene expression, no major differences were seen between the other horses. Possibly other factors such as the saturation of the P-gp as well as the role of other efflux transporters may play a role in these processes. At substrate concentrations which saturate the P-gp, oral absorption is mainly influenced by passive diffusion. By means of a pharmacological simulation it could be demonstrated that when the intestinal P-gp is saturated, the P‑gp at the blood-brain barrier (BBB) plays an increasingly important role in blood ivermectin levels. In this case a high P-gp expression at the BBB leads to an increased brain efflux of ivermectin and therefore to higher ivermectin plasma levels. A simultaneously high P-gp-mediated ivermectin efflux in the liver and kidney is responsible for a higher clearance. Due to the mutual compensation of the effects of P-gp-mediated transport at the blood-brain barrier and in the liver and kidney, no significant differences can be simulated for an altered MDR-1 gene expression in the case of saturated intestinal P-gp. This could offer an explanation for the lack of a significant difference in the measured plasma concentrations of ivermectin for the horses with high and low MDR-1 gene expression. As ivermectin is also a substrate for the multidrug resistance associated proteins (MRP) 1, 2 and 3 as well as for BCRP (Breast Cancer Resistance Protein), the expression levels of these proteins could mask effects on Ivermectin pharmacokinetics caused by P-gp. Further investigations with a larger number of horses might be carried out to determine the plasma concentration of ivermectin after its oral application. By screening a larger number of horses, more individuals with aberrant plasma concentrations could be identified. Further genetic analysis could help identify functional polymorphisms in the equine MDR-1 gene, as is the case in humans." @default.
• W2914219655 created "2019-02-21" @default.
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• W2914219655 date "2011-01-01" @default.
• W2914219655 modified "2023-09-24" @default.
• W2914219655 title "Untersuchungen zum Einfluss der MDR-1-Genexpression beim Pferd auf pharmakokinetische Prozesse am Beispiel von Ivermectin" @default.
• W2914219655 hasPublicationYear "2011" @default.
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