Vectorial transport of fexofenadine across Caco-2 cells: involvement of apical uptake and basolateral efflux transporters

Fexofenadine is a nonsedative antihistamine that exhibits good oral bioavailability despite its zwitterionic chemical structure and efflux by P-gp. Evidence exists that multiple uptake and efflux transporters play a role in hepatic disposition of fexofenadine. However, the roles of specific transporters and their interrelationship in intestinal absorption of this drug are unclear. This study was designed to elucidate vectorial absorptive transport of fexofenadine across Caco-2 cells involving specific apical uptake and efflux transporters as well as basolateral efflux transporters. Studies with cellular models expressing single transporters showed that OATP2B1 expression stimulated uptake of fexofenadine at pH 6.0. Apical uptake of fexofenadine into Caco-2 cells was decreased by 45% by pretreatment with estrone 3-sulfate, an OATP inhibitor, at pH 6.0 but not at pH 7.4, indicating that OATP2B1 mediates apical uptake of fexofenadine into these cells. Examination of fexofenadine efflux from preloaded Caco-2 cells in the presence or absence of (i) the MRP inhibitor MK-571 and (ii) the P-gp inhibitor GW918 showed that apical efflux is predominantly mediated by P-gp, with a small contribution by MRP2, whereas basolateral efflux is predominantly mediated by MRP3. These results also showed that while OSTαβ is functionally active in the basolateral membrane of Caco-2 cells, it does not play a role in the export of fexofenadine. MK-571 decreased the absorptive transport of fexofenadine by 17%. However, the decrease in absorptive transport by MK-571 was 42% when P-gp was inhibited by GW918. The results provide a novel insight into a vectorial transport system mainly consisting of apical OATP2B1 and basolateral MRP3 that may play an important role in delivering hydrophilic anionic and zwitterionic drugs such as pravastatin and fexofenadine into systemic circulation upon oral administration.     

Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: in vitro/in vivo case studies

The intestinal efflux pump, P-glycoprotein (P-gp), located in the apical membranes of intestinal absorptive cells, can reduce the bioavailability of a wide range of drugs which are substrates for this membrane transporter. In addition to anticancer and anti-HIV drugs, NCEs for other disease indications are P-gp substrates and there is considerable interest in inhibiting P-gp and thus increasing the bioavailability of these molecules. In this review article, an overview of P-gp and its role in drug transport and absorption will be presented first and then formulation strategies to effectively inhibit P-gp will be discussed and compared. These strategies independently and in combination, are: (a) coadministration of another P-gp substrate/specific inhibitor, and (b) incorporation of a nonspecific lipid and/or polymer excipient in the formulation. The first approach, although very effective in inhibiting P-gp, utilizes a second active compound in the formulation and thus imposes regulatory constraints and long development timelines on such combination products. Excipient inhibitors appear to have minimal nonspecific pharmacological activity and thus potential side effects of specific active compound inhibitors can be avoided. Case studies will be presented where specific active compounds, surfactants, polymers, and formulations incorporating these molecules are shown to significantly improve the intestinal absorption of poorly soluble and absorbed drugs as a result of P-gp inhibition and enhanced drug transport in vitro.     

The emerging role of P-glycoprotein inhibitors in drug delivery: a patent review

INTRODUCTION: The ATP-binding cassette superfamily contains membrane transporter proteins that transport a wide range of diverse compounds across cellular membranes. The P-glycoprotein (P-gp) is an important member of this family and a multi-specific drug efflux transporter that plays a significant role in governing the bioavailability of many clinically active drugs. The inhibition of this efflux transporter by various P-gp inhibitors forms a distinctive approach in improving bioavailability and conquering drug resistance. Most P-gp inhibitors exhibit limitations associated with their safety and unwanted pharmacokinetic interactions, thereby restraining their clinical applicability. AREAS COVERED: This review explores the investigations on the feasibility and applicability of various classes of P-gp inhibitors as described in recent patents for enhanced drug delivery. EXPERT OPINION: Several candidates presently under development look promising as P-gp inhibitors, e.g., tariquidar and elacridar. Pharmaceutical excipients currently constitute the most promising class of P-gp inhibitors and are considered safe and pharmaceutically acceptable for use in formulations. In addition, lipid-based excipients and thiolated polymers play an active role in affecting P-gp-mediated transport not only by altering the membrane fluidity or ATPase activity but by down regulating P-gp expression. An additional overture such as the prodrug derivatization of P-gp substrates is a feasible approach to bypass P-gp-mediated efflux.     

Transporter-mediated drug-drug interactions

Drug-drug interactions are a serious clinical issue. An important mechanism underlying drug-drug interactions is induction or inhibition of drug transporters that mediate the cellular uptake and efflux of xenobiotics. Especially drug transporters of the small intestine, liver and kidney are major determinants of the pharmacokinetic profile of drugs. Transporter-mediated drug-drug interactions in these three organs can considerably influence the pharmacokinetics and clinical effects of drugs. In this article, we focus on probe drugs lacking significant metabolism to highlight mechanisms of interactions of selected intestinal, hepatic and renal drug transporters (e.g., organic anion transporting polypeptide [OATP] 1A2, OATP2B1, OATP1B1, OATP1B3, P-gp, organic anion transporter [OAT] 1, OAT3, breast cancer resistance protein [BCRP], organic cation transporter [OCT] 2 and multidrug and toxin extrusion protein [MATE] 1). Genotype-dependent drug-drug interactions are also discussed.     

Effect of fruit juices on the oral bioavailability of fexofenadine in rats

Fexofenadine has been identified as a substrate for both the efflux transporter, P-glycoprotein (P-gp), as well as the influx transporter, organic anion transporting polypeptide (OATP). Clinical studies in humans showed that fruit juices reduced the oral bioavailability of fexofenadine by preferentially inhibiting OATP over P-gp. The objective of this study was to investigate the effects of fruit juices on the oral absorption of fexofenadine in rats to establish a preclinical fruit juice-drug interaction model. In rats, fexofenadine was excreted unchanged in the urine, bile, and gastrointestinal tract, indicating minimal metabolism, making it an ideal probe to study transport processes. Coadministration of fexofenadine with ketoconazole, a P-gp inhibitor, increased the oral exposure of fexofenadine by 187%. In contrast, coadministration of fexofenadine with orange juice or apple juice to rats decreased the oral exposure of fexofenadine by 31 and 22%, respectively. Increasing the quantity of orange or apple juice administered further decreased the oral exposure of fexofenadine, by 40 and 28%, respectively. This reduction in fexofenadine bioavailability was moderate compared to that seen in humans. These findings suggest that in rats fruit juices may also preferentially inhibit OATP rather than P-gp-mediated transport in fexofenadine oral absorption, albeit to a lesser extent than observed in humans. This fruit juice--drug interaction rat model may be useful in prediction of potential food--drug interactions in humans for drug candidates.     

P-Glycoprotein- and cytochrome P-450-mediated herbal drug interactions

P-Glycoprotein (P-gp), the most extensively studied ATP-binding cassette transporter, functions as a biological barrier by extruding toxic substances and xenobiotics out of cells. Drug efflux pumps such as P-gp play a functional role in determining the pharmacokinetics of drugs administered by oral and parenteral routes. Determining the activity of drug efflux transport proteins has important implications in the identification of substrates and/or inhibitors. The significant role of the small intestine in reducing the oral bioavailability of drugs is due to metabolic enzymes and efflux transporters. The role of cytochrome P-450 3A (CYP3A) and P-gp in intestinal drug disposition has been highlighted. This review examines the structure, localisation and functional role of P-gp, the mechanism of drug efflux and drug-herb interactions.     

How significant is the role of P-glycoprotein in drug absorption and brain uptake?

Although P-glycoprotein (P-gp) is highly expressed in both intestinal epithelial cells and endothelial cells of brain capillaries, and functions as an efflux transporter in both organs, the impact of P-gp on intestinal absorption and brain uptake of drugs is quantitatively very different. The effect of P-gp on drug absorption is not quantitatively as important as suggested. Many drugs are good human P-gp substrates and yet exhibit reasonable oral bioavailability. In contrast, P-gp plays a quantitatively very important role in blocking the brain uptake of P-gp substrates. This review provides an overview of the role of P-gp in drug absorption and brain uptake, and explores possible factors that may explain the quantitative differences in the impact of P-gp on drug absorption and brain uptake.     

Fruit juice inhibition of uptake transport: a new type of food-drug interaction

A new type of interaction in which fruit juices diminish oral drug bioavailability through inhibition of uptake transport is the focus of this review. The discovery was based on an opposite to anticipated finding when assessing the possibility of grapefruit juice increasing oral fexofenadine bioavailability in humans through inhibition of intestinal MDR1-mediated efflux transport. In follow-up investigations, grapefruit or orange juice at low concentrations potentially and selectively inhibited in vitro OATP1A2-mediated uptake compared with MDR1-caused efflux substrate transport. These juices at high volume dramatically depressed oral fexofenadine bioavailability. Grapefruit was the representative juice to characterize the interaction subsequently. A volume–effect relationship study using a normal juice amount halved average fexofenadine absorption. Individual variability and reproducibility data indicated the clinical interaction involved direct inhibition of intestinal OATP1A2. Naringin was a major causal component suggesting that other flavonoids in fruits and vegetables might also produce the effect. Duration of juice clinical inhibition of fexofenadine absorption lasted more than 2 h but less than 4 h indicating the interaction was avoidable with appropriate interval of time between juice and drug consumption. Grapefruit juice lowered the oral bioavailability of several medications transported by OATP1A2 (acebutolol, celiprolol, fexofenadine, talinolol, L-thyroxine) while orange juice did the same for others (atenolol, celiprolol, ciprofloxacin, fexofenadine). Juice clinical inhibition of OATP2B1 was unresolved while that of OATP1B1 seemed unlikely. The interaction between grapefruit juice and etoposide also seemed relevant. Knowledge of both affected uptake transporter and drug hydrophilicity assisted prediction of the clinical interaction with grapefruit or orange juice.     

Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs

BACKGROUND: Biliary excretion is a major elimination route of many drugs and their metabolites. Hepatobiliary elimination is a vectorial process involving uptake transporters in the basolateral hepatocyte membrane, possibly Phase I and Phase II metabolizing enzymes, and ATP-dependent efflux pumps in the apical hepatocyte membrane. OBJECTIVES: Because many drugs and their metabolites are anions, this review focuses on transporters involved in their hepatocellular uptake (members of the organic anion transporting polypeptide (OATP) family) and biliary elimination (apical conjugate efflux pump ABCC2/MRP2). METHODS: The molecular and functional characteristics of the human OATP and ABCC/MRP transporters are presented, including a detailed overview of endogenous and drug substrates. Examples illustrate the interplay of transporters with Phase II conjugating enzymes. Model systems to study the vectorial transport of organic anions are also discussed. RESULTS/CONCLUSIONS: OATP uptake transporters, conjugating enzymes, and ABCC2/MRP2 work in concert to enable the hepatobiliary elimination of anionic drugs and their metabolites. It is increasingly important to understand how genetic variants of these transporters and enzymes influence the interindividual variability of drug elimination.     

Transporter targeted drug delivery

The pharmacological behavior of various drugs is severely affected by biological barriers such as epithelial tight junctions, efflux proteins and metabolizing enzymes. Apart from the biological barriers, physicochemical properties of drug molecules such as molecular weight, lipophilicity, surface charge and solubility also play an important role in absorption characteristics of drug candidates. Pharmacological properties affected by efflux pumps such as P-gp and MRPs include bioavailability, hepatobiliary and urinary excretion of drugs as well as drug metabolites. This leads to sub-therapeutic concentrations of various potential drugs at the target site. One of the strategies to overcome these biological barriers is transporter targeted prodrug design. Prodrug derivatization targeting membrane transporters and receptors improves drug absorption. Various prodrugs which have been synthesized so far demonstrated enhanced bioavailability and tissue specificity. This review mainly focuses on the efflux pumps which play an important role in drug absorption and a few strategies to overcome these efflux pumps.     

A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans

BACKGROUND: The potential absorption-limiting effect of intestinal efflux transporters such as P-glycoprotein (P-gp) has been well recognized, primarily based on results of numerous Caco-2 cell studies showing that flux, permeability, or transport clearance of drugs from the basolateral to the apical (B --> A) compartment is greater than that from the apical to the basolateral (A --> B) compartment. Except for very limited examples such as celiprolol, talinolol, pafenolol and paclitaxel, the potential clinical impact of these transporters on oral absorption of the vast number of commonly prescribed drug substrates in humans has not been closely examined to date. OBJECTIVE: To evaluate whether these efflux transporters may play a significant role in limiting oral absorption of 13 commonly used drugs (digoxin, etoposide, felodipine, fexofenadine, furosemide, indinavir, losartan, nadolol, propranolol, ritonavir, saquinavir, tacrolimus, and verapamil) in humans. METHODS: Drug absorption properties such as the rate (as judged by the Cmax and tmax) and extent (as judged by AUC or urinary excretion of drugs) of absorption as a function of dose, as well as the completeness of oral absorption were obtained from the literature. RESULTS: The absorption properties of these 13 drugs are not consistent with absorption-retarding expectations from in vitro studies because they all show apparent dose-independent kinetics in absorption or bioavailability and completeness of oral absorption is shown for most of the drugs evaluated. CONCLUSIONS: In spite of being substrates of intestinal efflux transporters such as P-gp, the in vivo oral absorption of 13 drugs examined apparently is not significantly impeded by efflux transporters. Thus, there may exist an apparent discrepancy between in vitro "expectations" and in vivo results; potential reasons for this are discussed. The present findings, however, do not de-emphasize potential in vivo importance of efflux transporters in affecting (increasing or decreasing) oral absorption of certain substrate drugs, especially those with low to moderate intestinal permeability and with low therapeutic index, or the importance of efflux transporters in the study of mechanisms of drug absorption and some potentially clinically significant drug-drug and drug-food interactions.     

Does inhibition of P-glycoprotein lead to drug–drug interactions?

Permeability-glycoprotein (Pgp) is a drug transporter responsible for the efflux of xenobiotics out of cells that influence the pharmacokinetics of numerous drugs. However, the role of this transporter in drug-drug interactions is still poorly studied even though a lot of P-glycoprotein substrates and P-glycoprotein inhibitors are identified among drugs of standard usage. On one hand, Pgp is distributed within a lot of organs and tissues implicated in the absorption or excretion of xenobiotics, and drug-drug interactions with this protein may increase the bioavailability of simultaneously administered active drugs. On the other hand, Pgp is linked to the integrity of blood-tissue barriers, such as the blood-brain barrier or placenta, and a partial blockage of Pgp could be responsible for a new drug distribution in the organism with possible increase of drug rates in organs behind these barriers. Therefore, concomitant administration of substrates and Pgp inhibitors would modify drug pharmacokinetics by increasing bioavailability and organ uptake, leading to more adverse drug reactions and toxicities. Consequently, the identification and comprehension of these drug-drug interactions remain important keys to risk assessment.     

DM27, an enaminone, modifies the in vitro transport of antiviral therapeutic agents

OBJECTIVE: For most antiviral drugs, low or variable bioavailability is attributed to poor absorption, susceptibility to efflux, or first pass metabolism. Enaminones are beta dicarbonyl compounds, which display P-glycoprotein (P-gp) substrate properties with high efflux ratios. This study investigates the influence of DM27, an enaminone, on the in vitro transport of antiviral agents and the possibility of using DM27 as a P-gp inhibitor to prevent the efflux of certain antiretroviral agents. METHODS: The transport of [3H]amprenavir, [3H]saquinavir, [3H]ritonavir, [14C]zidovudine (AZT) and [3H]acyclovir was evaluated across Caco-2 cells with DM27 (10(-10)-10(-4) M). In addition, the effect of DM27 (10(-6) M) on the transport of transcellular and paracellular markers was tested to evaluate its influence on these transport pathways. The apparent permeability coefficient (Papp) for each drug or marker was calculated with/without DM27 and toxicity evaluation for DM27 was performed using the MTS assay. RESULTS: The mean Papp for the investigated antiviral agents significantly increased by 22%-51% after DM27 incubation without any toxicity to the Caco-2 cells. In addition, DM27 did not influence the transcellular or paracellular transport of propranolol and mannitol, respectively. CONCLUSIONS: DM27, an enaminone, increased the transport of antiretroviral drugs and acyclovir in a nontoxic manner without affecting the paracellular or transcellular transport of these drugs. This study suggests that DM27 may be used as a P-gp efflux inhibitor to enhance the oral bioavailability of antiviral drugs and that drug-drug interactions will most probably be encountered upon co-administration of P-gp substrate drugs with enaminones.     

Role of transport proteins in drug absorption, distribution and excretion

1. The molecular and functional characterization of transport proteins is emerging rapidly and significant numbers of drugs have been shown to be substrates or inhibitors. The purpose of this review is to highlight the in vivo preclinical and clinical evidence that supports a role for transport proteins in attenuating the absorption, distribution and excretion (ADE) of drugs. 2. For absorption, a clear role has emerged for P-glycoprotein in limiting permeability across the gastrointestinal tract. As a result, a wide variety of drugs suffer from incomplete, variable and non-linear absorption. Similarly, at the blood-brain barrier a range of drugs has limited brain penetration due to P-glycoprotein-mediated efflux, which can limit therapeutic effectiveness of CNS agents. In the liver, transport proteins are present on the sinusoidal membrane that can be the rate-limiting step in hepatic clearance for some drugs. Mechanistic studies clearly suggest a key role and broad substrate specificity for the OATP family of sinusoidal transporters. Mainly ATP-dependent transport proteins such as P-glycoprotein and MRP2 govern active biliary excretion. 3. Drug-drug interactions have been demonstrated involving inhibition or induction of transport proteins. Clinically significant interactions in the gastrointestinal tract and kidney have been observed with inhibitors such as ketoconazole, erythromycin, verapamil, quinidine, probenecid and cimetidine. Clinically significant inhibition at the blood-brain barrier is more difficult to demonstrate, relying on pharmacodynamic and toxicodynamic changes, but an example is quinidine increasing loperamide-induced central effects in humans. 4. This review highlights the emerging role of transport proteins in ADE of drugs and suggests these need to be considered, in drug discovery and development, with respect to variability in drug disposition and response.     

Evaluation of drug interactions with P-glycoprotein in drug discovery: in vitro assessment of the potential for drug-drug interactions with P-glycoprotein

The pharmacological effects of a drug are highly dependent on the absorption, metabolism, elimination, and distribution of the drug. In the past few years it has become apparent that transport proteins play a major role in regulating the distribution, elimination and metabolism of some drugs. As a consequence of our new understanding of the influence of transport proteins on the pharmacokinetic and pharmacodynamic behavior of drugs, increasing attention has been focused on the potential for drug-drug interactions arising from interactions with drug transport proteins. The efflux transporter P-glycoprotein (P-gp) has received the most attention with regard to its role in restricting drug absorption and distribution and as a potential source for variability in drug pharmacokinetics and pharmacodynamics. This review will focus on the evaluation of drug candidates to assess the potential for drug interactions at the level of P-gp. We will discuss the role of P-gp in drug disposition, the biochemistry of P-gp efflux as it relates to model systems to study drug interactions with P-gp, and the implementation of P-gp assay models within the drug discovery process.     

Uptake transporters of the human OATP family: molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms

Organic anion transporting polypeptides (OATPs, gene family: SLC21/SLCO) mediate the uptake of a broad range of substrates including several widely prescribed drugs into cells. Drug substrates for members of the human OATP family include HMG-CoA-reductase inhibitors (statins), antibiotics, anticancer agents, and cardiac glycosides. OATPs are expressed in a variety of different tissues including brain, intestine, liver, and kidney, suggesting that these uptake transporters are important for drug absorption, distribution, and excretion. Because of their wide tissue distribution and broad substrate spectrum, altered transport kinetics, for example, due to drug-drug interactions or due to the functional consequences of genetic variations (polymorphisms), can contribute to the interindividual variability of drug effects. Therefore, the molecular characteristics of human OATP family members, the role of human OATPs in drug-drug interactions, and the in vitro analysis of the functional consequences of genetic variations in SLCO genes encoding OATP proteins are the focus of this chapter.     

Role of transport proteins in drug absorption,distribution and excretion

1. The molecular and functional characterization of transport proteins is emerging rapidly and significant numbers of drugs have been shown to be substrates or inhibitors. The purpose of this review is to highlight the in vivo preclinical and clinical evidence that supports a role for transport proteins in attenuating the absorption, distribution and excretion (ADE) of drugs. 2. For absorption, a clear role has emerged for P-glycoprotein in limiting permeability across the gastrointestinal tract. As a result, a wide variety of drugs suffer from incomplete, variable and non-linear absorption. Similarly, at the blood-brain barrier a range of drugs has limited brain penetration due to P-glycoprotein-mediated efflux, which can limit therapeutic effectiveness of CNS agents. In the liver, transport proteins are present on the sinusoidal membrane that can be the rate-limiting step in hepatic clearance for some drugs. Mechanistic studies clearly suggest a key role and broad substrate specificity for the OATP family of sinusoidal transporters. Mainly ATP-dependent transport proteins such as P-glycoprotein and MRP2 govern active biliary excretion. 3. Drug-drug interactions have been demonstrated involving inhibition or induction of transport proteins. Clinically significant interactions in the gastrointestinal tract and kidney have been observed with inhibitors such as ketoconazole, erythromycin, verapamil, quinidine, probenecid and cimetidine. Clinically significant inhibition at the blood-brain barrier is more difficult to demonstrate, relying on pharmacodynamic and toxicodynamic changes, but an example is quinidine increasing loperamide-induced central effects in humans. 4. This review highlights the emerging role of transport proteins in ADE of drugs and suggests these need to be considered, in drug discovery and development, with respect to variability in drug disposition and response.     

Co-delivery of rapamycin- and piperine-loaded polymeric nanoparticles for breast cancer treatment

P-glycoprotein (P-gp) efflux is the major cause of multidrug resistance (MDR) in tumors when using anticancer drugs, moreover, poor bioavailability of few drugs is also due to P-gp efflux in the gut. Rapamycin (RPM) is in the clinical trials for breast cancer treatment, but its P-gp substrate property leads to poor oral bioavailability and efficacy. The objective of this study is to formulate and evaluate nanoparticles of RPM, along with a chemosensitizer (piperine, PIP) for improved oral bioavailability and efficacy. Poly(d,l-lactide-co-glycolide) (PLGA) was selected as polymer as it has moderate MDR reversal activity, which may provide additional benefits. The nanoprecipitation method was used to prepare PLGA nanoparticles with particle size below 150?nm, loaded with both drugs (RPM and PIP). Prepared nanoparticles showed sustained in vitro drug release for weeks, with initial release kinetics of zero order with non-Fickian transport, subsequently followed by Higuchi kinetics with Fickian diffusion. An everted gut sac method was used to study the effect of P-gp efflux on drug transport. This reveals that the uptake of the RPM (P-gp substrate) has been increased in the presence of chemosensitizer. Pharmacokinetic studies showed better absorption profile of RPM from polymeric nanoparticles compared to its suspension counterpart and improved bioavailability of 4.8-folds in combination with a chemosensitizer. An in vitro cell line study indicates higher efficacy of nanoparticles compared to free drug solution. Results suggest that the use of a combination of PIP with RPM nanoparticles would be a promising approach in the treatment of breast cancer.     

The emerging role of P-glycoprotein inhibitors in drug delivery: a patent review

Introduction: The ATP-binding cassette superfamily contains membrane transporter proteins that transport a wide range of diverse compounds across cellular membranes. The P-glycoprotein (P-gp) is an important member of this family and a multi-specific drug efflux transporter that plays a significant role in governing the bioavailability of many clinically active drugs. The inhibition of this efflux transporter by various P-gp inhibitors forms a distinctive approach in improving bioavailability and conquering drug resistance. Most P-gp inhibitors exhibit limitations associated with their safety and unwanted pharmacokinetic interactions, thereby restraining their clinical applicability.

Areas covered: This review explores the investigations on the feasibility and applicability of various classes of P-gp inhibitors as described in recent patents for enhanced drug delivery.

Expert opinion: Several candidates presently under development look promising as P-gp inhibitors, e.g., tariquidar and elacridar. Pharmaceutical excipients currently constitute the most promising class of P-gp inhibitors and are considered safe and pharmaceutically acceptable for use in formulations. In addition, lipid-based excipients and thiolated polymers play an active role in affecting P-gp-mediated transport not only by altering the membrane fluidity or ATPase activity but by down regulating P-gp expression. An additional overture such as the prodrug derivatization of P-gp substrates is a feasible approach to bypass P-gp-mediated efflux.     

Emerging significance of P-glycoprotein in understanding drug disposition and drug interactions in psychopharmacology

P-glycoprotein (P-gp) is a member of the superfamily of energy-dependent efflux protein pumps involved in the transport of a wide variety of endogenous and exogenous substrates. The role of P-gp has been extensively studied in the development of multidrug resistance (MDR) in cancer cells during chemotherapy. However, recent data suggest that P-gp is also present in normal tissue, such as the gut, blood-brain barrier, lymphocytes, liver, kidney, and other organs, where it plays a role in the absorption, distribution, metabolism, and elimination of a multitude of drugs. Psychotropic drugs, as well as many other drugs, act as substrates, inhibitors, or inducers of P-gp function. While there is a growing interest in developing inhibitors of this transporter as an approach to increasing drug bioavailability, the utility of exploiting inducers of the protein is less clear. Changes in P-gp transport activity have recently been linked to clinically significant drug-drug and drug-herb interactions. Because of its wide tissue distribution and its effect on drug disposition, clinicians should recognize the potential impact of P-gp modulation on the therapeutic efficacy and adverse events of psychopharmacologic agents that are substrates for this transporter. More research is needed in the field of psychopharmacology to classify central nervous system-active P-gp substrates and to characterize the utility of modulating P-gp activity at the blood-brain barrier.