Importance of P-glycoprotein for Drug–Drug Interactions

Abstract

P-glycoprotein (ABCB1) is one of the most extensively studied transporters regarding drug resistance and drug-drug interactions. P-glycoprotein is expressed in multiple key organs in drug disposition such as small intestine, blood-brain barrier, kidney, and liver. Therefore, P-glycoprotein mediated drug-drug interactions can occur at various organs and tissues. This chapter will mainly focus on drug-drug interactions that are mediated by the intestinal P-glycoprotein.During the last decade, many in vitro and in vivo studies reported that the induction or inhibition of P-glycoprotein can lead to drug-drug interactions. For instance, induction of the intestinal P-glycoprotein activity can cause reduced bioavailability of orally administered drugs and decreased therapeutic efficacy. On the other hand, the inhibition of the intestinal P-glycoprotein activity can lead to increased bioavailability, thus leading to an increased risk of adverse side effects.

Oral Absorption of Clarithromycin Is Nearly Abolished by Chronic Comedication of Rifampicin in Foals

“…RIF is a prototype ligand for the nuclear PXR receptor that regulates many drug-metabolizing enzymes and multidrug transport proteins in the small intestine and the liver (Handschin and Meyer, 2003;Glaeser, 2011;Oswald et al, 2011b;Tirona, 2011). Induction of hepatic CYP3A4 in our study was confirmed by a significant increase in the 4␤-hydroxycholesterol/cholesterol plasma concentration ratio, an accepted endogenous metric for hepatic CYP3A4 activity in vivo (Yang and Rodrigues, 2010).…”

Toxicokinetics of lefetamine and derived diphenylethylamine designer drugs—Contribution of human cytochrome P450 isozymes to their main phase I metabolic steps

“…The ATP-dependent P-glycoprotein (P-gp) is 253 responsible e.g. for the resistance of cancer cells against medication or can be the cause for 254 relevant interactions between two drugs (Glaeser, 2011). NPDPA was tested for its activity 255 towards P-gp in a cell monolayer system after showing stimulation of P-gp ATPase activity 256 (Meyer et al, 2015).…”

Efectos de los inductores antiepilépticos en la neuropsicofarmacología: una cuestión ignorada. Parte II: cuestiones farmacológicas y comprensión adicional

“…La quinidina y la claritromicina han demostrado ser inhibidores de la digoxina, y se cree que esta inhibición está explicada por la potente inhibición de la P-gp 94,95 . Sin embargo, la quinidina es también un potente inhibidor del CYP2D6, y la claritromicina es un potente inhibidor de CYP3A4.…”

“…De igual modo, la rifampicina y el hipérico parecen ser inductores de la P-gp, según han demostrado a través de los efectos de ciertos fármacos tales como la digoxina 87,95 y la fexofenadina 95 , que son sustratos de la P-gp aunque no son metabolizados por el CYP3A4. La complejidad de estudiar los inductores de la P-gp se demuestra por el hecho de que la rifampicina puede ser inicialmente un inhibidor de P-gp e incrementar la absorción de la digoxina, aunque tras cierto tiempo (una semana) puede ser un inductor de P-gp y disminuir su absorción 94 .…”