Role of P-Glycoprotein in Pharmacokinetics

Abstract

P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition. Because of its localisation, P-glycoprotein appears to have a greater impact on limiting cellular uptake of drugs from blood circulation into brain and from intestinal lumen into epithelial cells than on enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. However, the relative contribution of intestinal P-glycoprotein to overall drug absorption is unlikely to be quantitatively important unless a very small oral dose is given, or the dissolution and diffusion rates of the drug are very slow. This is because P-glycoprotein transport activity becomes saturated by high concentrations of drug in the intestinal lumen. Because of its importance in pharmacokinetics, P-glycoprotein transport screening has been incorporated into the drug discovery process, aided by the availability of transgenic mdr knockout mice and in vitro cell systems. When applying in vitro and in vivo screening models to study P-glycoprotein function, there are two fundamental questions: (i) can in vitro data be accurately extrapolated to the in vivo situation; and (ii) can animal data be directly scaled up to humans? Current information from our laboratory suggests that in vivo P-glycoprotein activity for a given drug can be extrapolated reasonably well from in vitro data. On the other hand, there are significant species differences in P-glycoprotein transport activity between humans and animals, and the species differences appear to be substrate-dependent. Inhibition and induction of P-glycoprotein have been reported as the causes of drug-drug interactions. The potential risk of P-glycoprotein-mediated drug interactions may be greatly underestimated if only plasma concentration is monitored. From animal studies, it is clear that P-glycoprotein inhibition always has a much greater impact on tissue distribution, particularly with regard to the brain, than on plasma concentrations. Therefore, the potential risk of P-glycoprotein-mediated drug interactions should be assessed carefully. Because of overlapping substrate specificity between cytochrome P450 (CYP) 3A4 and P-glycoprotein, and because of similarities in P-glycoprotein and CYP3A4 inhibitors and inducers, many drug interactions involve both P-glycoprotein and CYP3A4. Unless the relative contribution of P-glycoprotein and CYP3A4 to drug interactions can be quantitatively estimated, care should be taken when exploring the underlying mechanism of such interactions.

Transport of digoxin-loaded Polymeric Nanoparticles Across BeWo cells, an In Vitro Model of Human Placental Trophoblast

“…Although Figure 3 also demonstrates that the permeability of digoxin across trophoblast cells increases in the presence of verapamil, an efflux transporter inhibitor, this is unlikely to represent an acceptable clinical approach. The coadministration of P-gp inhibitors in order to increase the delivery of a drug that is a substrate of P-gp may lead to serious side effects associated with off-target tissue accumulation, such as n eurotoxicity due to inhibition of P-gp in the brain [38].…”

Synthesis, Antimicrobial, Antitubercular and Cheminformatic Studies of 2-(1-Benzofuran-2-Yl)-N'-[(3z)-2-Oxo-1, 2-Dihydro-3h-Indol-3-Ylidene] Quinoline-4-Carbohydrazide and Its Derivatives

“…The CNS activity was computed on-2 (inactive) to+2 (active) which showed all the molecules are displayed within the acceptable range. ) and Caco-2 cell permeability (PCaco-2) in between the range of-2 poor absorption and+2 more absorption show that the compounds are more permeable in the intestine and helps for good transport of drug metabolic compounds [31]. Table 6: ADME and pharmacological parameters prediction for the ligands (1 benzofuran-2-yl)-N'-[(3Z)-2-oxo-1, 2-dihydro-3H-indol-3ylidene] quinoline-4 carbohydrazide and its derivatives 2(a-b), 3(a-b), 4(a-b), 5(a-b) and 6(a-b) a Predicted blood/brain barrier partition coefficient (1-high penetration, 2-medium penetration and 3-Low penetration).…”

“…The statistical calculation for lead molecules includes surface area, geometry and fingerprint properties which help to understand biologically important end points. Aqueous solubility (PlogS), Blood-brain barrier penetration (QlogBB), intestinal absorption (logHIA), hepatotoxicity, Caco-2 cell permeability (QPPCaco) also helps to predict the toxicity of lead molecules [31] with intraperitoneal, oral, intravenous and subcutaneous. The in silico study enables to decide the safety and efficacy of active molecules take up the molecule for in-depth studies.…”

Editorial: Clopidogrel and the C3435T Single Nucleotide Polymorphism and Breast Cancer Therapies

“…In addition to anticancer drugs, P-glycoprotein is also involved in transporting other groups of drugs and, therefore, mutations in this gene [3] may influence the pharmacokinetics of different drugs. Vavlukis et al in their research article study the influence of the single nucleotide polymorphism C3435T in the MDR1 gene on the clinical outcomes in patients with coronary artery disease who is receiving clopidogrel treatment.…”