P-Glycoprotein and Bioavailability-Implication of Polymorphism

Abstract

P-Glycoprotein (P-gp) may have a significant impact on systemic and tissue/cellular bioavailability of drugs because it functions as an "anti-absorption" mechanism that effluxes drug molecules out of the lipid bilayer and cytoplasm. The ability to reduce bioavailability at the tissue/cellular level was first discovered during the investigation of the causes of multidrug resistance (MDR) in cancer chemotherapy. Initially, it was thought that MDR is only caused by P-gp. Recently, many other transporters such as multidrug resistance-related protein (MRP) have also been identified. The ability of P-gp to impact systemic drug bioavailability was only recently recognized. Dr. Alfred Schinkel's group was first to show a significant improvement in the systemic bioavailability of several drugs in the MDR1 knockout mice. The same group also discovered that the blood-brain barrier (BBB) has a very high expression level of P-gp, and that this protein is necessary to restrict the entrance of various drug molecules into the central nervous system (CNS). Polymorphism in the normal human cells has not been reported, but it has been discovered in human cancer cells. Functional implication of P-gp polymorphism in changing the tissue bioavailability has been studied in rodents. These studies strongly support the role of P-gp in restricting tissue bioavailability of anticancer drugs. These studies also support the effectiveness of P-gp in limiting CNS toxicity of the cytotoxic drugs. The functional implication of P-gp on systemic bioavailability is much less well defined in humans, although it appears to be quite obvious in MDR1 knockout mice. Pharmacokinetic models clearly suggest that a change in the absorption rate will have a significant impact on systemic blood level of a drug. However, whether functionally significant polymorphisms of P-gp exist in humans has not been determined. If they do exist, they will surely impact on both systemic bioavailability and drug interaction potentials of many drugs. In the drug development process, several models may be used to select a lead compound that may or may not interact with P-gp, depending on whether the interaction is desirable. Several inhibitors of P-gp are currently on the clinical trial stage. Natural inhibitors of P-gp have also been discovered. There is no doubt that these new developments will have significant impact on the bioavailability of a variety of anticancer and CNS drugs in the next decades.

Coupling of Conjugating Enzymes and Efflux Transporters: Impact on Bioavailability and Drug Interactions

“…Additionally, some of the efflux transporters (e.g. p-glycoprotein) may be capable of sequestering metabolites in the cytosolic domain and then pump them out once the complex merged into the cell membrane [9]. Moreover, we have shown that multiple transporters are involved in the cellular excretion of phase II conjugates, creating a network that is far more complex than that depicted in Fig.…”

“…Substrates of P-gp have diverse chemical structures, but the vast majority is lipophilic planar molecules. Most P-gp substrates are uncharged, but a few weakly basic or acidic compounds such as methotrexate are also transported [9].…”

Natural polyphenol disposition via coupled metabolic pathways

“…As has been shown by us in the previous review [90] parent compound itself may also be subjected to efflux at the apical side or basolateral side or both [101]. Moreover, some of the efflux transporters, e.g., p-glycoprotein, may be capable of sequestering metabolites in the cytosolic domain and then pump them out once the complex merged into the cell membrane [102]. Lastly, we and other investigators have found that multiple transporters, e.g., MRP2, OAT, are involved in the cellular excretion of phase II conjugates of natural polyphenols [51,99,103,104].…”

Functional Characterization of Coding Polymorphisms in the HumanMDR1 Gene Using a Vaccinia Virus Expression System

“…Several recent reports indicate that polymorphisms are relatively common in the human MDR1 gene (Yoshimoto et al, 1988;Mickley et al, 1998;Decleves et al, 2000;Hoffmeyer et al, 2000;Liu and Hu 2000;Ameyaw et al, 2001;Brinkmann et al, 2001;Cascorbi et al, 2001;Hitzl et al, 2001;Ito et al, 2001;Kerb et al, 2001;Kim et al, 2001;Schaeffeler et al, 2001). This finding has stimulated interest in whether common coding polymorphisms affect function of P-gp and/or whether polymorphic variants are linked to altered drug pharmacokinetics.…”