Involvement Of P-glycoprotein Research Articles

A Comparative Study of Influence of Different Polymers on Lumefantrine: Piperine Solid Dispersion

To improve the oral delivery of biopharmaceutical classification system (BCS) class II drugs, solid dispersions techniques are generally adopted in drug product develooment in pharmaceuticals. The choice of polymer in these designs significantly affects a drug’s solubility and dissolution properties. The crystalline nature and the involvement of P-glycoprotein in active ingredient efflux further hinder drug absorption and bioavailability. In this study, solid dispersion (SD) of an antimalarial drug (lumefantrine) combined with piperine (a P-gp and CYP3A4 inhibitor), was created using different polymeric carriers: Soluplus, Klucel, Poloxamer, Povidone/PVP K30 (PVP), and Copovidone/Kollidon® VA64 (KOL). Among these, LUMF-PIP solid dispersion with SOL exhibited the maximum water solvency and fastest release across various media. These findings indicate that the choice of polymeric carrier significantly impacts LUMF’s solubility and dissolution behavior in solid dispersion. SOL emerges as the most promising polymer for enhancing LUMF’s solubility and dissolution, ultimately leading to improved bioavailability upon oral administration.

Comparison of the permeability between conjugated estrogens and atenolol in rat in situ single-pass intestinal perfusions model and in Caco-2 cell monolayers

To investigate whether Conjugated Estrogens (CEs) as a potential drug with medium or high permeability. Effective permeability (Peff) of CEs was studied in rat in situ single-pass intestinal perfusions (SPIP) model and apparent permeability (Papp) in Caco-2 cell monolayers model. Atenolol served as a standard reference for the medium of Peff and Papp. Further, the intestinal epithelial permeability of CEs was assessed across Caco-2 cell monolayers in both apical (AP)-basolateral (BL) and BL-AP directions, the effects of time and concentration of CEs and the involvement of P-Glycoprotein (P-gp) in CEs transport were also investigated. Results showed that Peff of CEs and atenolol in two different segments of rat intestine (the jejunum and the ileum) were comparable (P=NS). In Caco-2 cell model, Papp of CEs and atenolol at absorptive (AP-BL) direction were also similar. The transport of CEs was time- and concentration-dependent in the tested concentration range (from 80 to 500 μg/ml) and time points (from 15 to 120 min). CEs at the concentration of 200 μg/ml exhibited higher Papp at secretive direction (BL-AP) compared to that at AP-BL direction [(0.64 ± 0.16 vs. 0.25 ± 0.02) × 10−6 cm/s, P < 0.05]. P-gp inhibitors, verapamil and cyclosporin A, significantly increased passive transport of CEs at absorptive direction but decreased active transport at secretive direction, indicating that CEs is a substrate of P-gp. In summary, as the permeabilities (both Peff and Papp) of CEs and atenolol in SPIP and cell models were comparable, CEs can be considered as a drug with moderate permeability. CEs transport is time- and concentration-dependent and P-gp is able to mediate a CEs efflux.

Involvement of P-glycoprotein in α-Synuclein aggregate-induced inflammatory mediator release by brain pericytes

Involvement of P-glycoprotein in α-Synuclein aggregate-induced inflammatory mediator release by brain pericytes

P-Glycoprotein Inhibitor Tariquidar Plays an Important Regulatory Role in Pigmentation in Larval Zebrafish.

Zebrafish has emerged as a powerful model in studies dealing with pigment development and pathobiology of pigment diseases. Due to its conserved pigment pattern with established genetic background, the zebrafish is used for screening of active compounds influencing melanophore, iridophore, and xanthophore development and differentiation. In our study, zebrafish embryos and larvae were used to investigate the influence of third-generation noncompetitive P-glycoprotein inhibitor, tariquidar (TQR), on pigmentation, including phenotype effects and changes in gene expression of chosen chromatophore differentiation markers. Five-day exposure to increasing TQR concentrations (1 µM, 10 µM, and 50 µM) resulted in a dose-dependent augmentation of the area covered with melanophores but a reduction in the area covered by iridophores. The observations were performed in three distinct regions—the eye, dorsal head, and tail. Moreover, TQR enhanced melanophore renewal after depigmentation caused by 0.2 mM 1-phenyl-2-thiourea (PTU) treatment. qPCR analysis performed in 56-h post-fertilization (hpf) embryos demonstrated differential expression patterns of genes related to pigment development and differentiation. The most substantial findings include those indicating that TQR had no significant influence on leukocyte tyrosine kinase, GTP cyclohydrolase 2, tyrosinase-related protein 1, and forkhead box D3, however, markedly upregulated tyrosinase, dopachrome tautomerase and melanocyte inducing transcription factor, and downregulated purine nucleoside phosphorylase 4a. The present study suggests that TQR is an agent with multidirectional properties toward pigment cell formation and distribution in the zebrafish larvae and therefore points to the involvement of P-glycoprotein in this process.

Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein.

Drug-drug interaction was suggested to have played a role in the recent death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole antipsychotic/antidepressant combination therapy. Here, we investigated the possible involvement of P-glycoprotein (P-gp)-mediated interaction among these drugs, using in vitro methods. ATPase assay confirmed that pimozide is a P-gp substrate, and might act as a P-gp inhibitor at higher concentrations. The maximum transport rate (Jmax) and half-saturation concentration (Kt) for the carrier-mediated transport estimated by means of pimozide efflux assay using P-gp-overexpressing LLC-GA5-CoL150 cells were 84.9 ± 8.9 pmol/min/mg protein, and 10.6 ± 4.7 μM, respectively. These results indicate that pimozide is a good P-gp substrate, and it appears to have the potential to cause drug-drug interactions in the digestive tract at clinically relevant gastrointestinal concentrations. Moreover, sertraline or aripiprazole significantly decreased the efflux ratio of pimozide in LLC-GA5-CoL150 cells. Transport studies using Caco-2 cell monolayers were consistent with the results in LLC-GA5-CoL150 cells, and indicate that P-gp-mediated drug-drug interaction may occur in the gastrointestinal tract. Thus, P-gp inhibition by sertraline and/or aripiprazole may increase the gastrointestinal permeability of co-administered pimozide, resulting in an increased blood concentration of pimozide, which is known to be associated with an increased risk of QT prolongation, a life-threatening side effect.

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study.

Doxorubicin represents a valuable choice for different cancers, although the severe side effects occurring at the high effective dose limits its clinical use. In the present study, potential strategies to potentiate low-dose doxorubicin efficacy, including a metronomic schedule, characterized by a short and repeated exposure to the anticancer drug, and the combination with the natural chemosensitizing sesquiterpenes β-caryophyllene and β-caryophyllene oxide, were assessed in human hepatoma HepG2 cells. The involvement of P-glycoprotein (P-gp) in the HepG2–chemosensitization to doxorubicin was evaluated. Also, the direct interaction of caryophyllene sesquiterpenes with P-gp was characterized by molecular docking and dynamic simulation studies. A metronomic schedule allowed us to enhance the low-dose doxorubicin cytotoxicity and the combination with caryophyllane sesquiterpenes further potentiated this effect. Also, an increased intracellular accumulation of doxorubicin and rhodamine 123 induced by caryophyllane sesquiterpenes was found, thus suggesting their interference with P-gp function. A lowered expression of P-gp induced by the combinations, with respect to doxorubicin alone, was observed too. Docking studies found that the binding site of caryophyllane sesquiterpene was next to the ATP binding domain of P-gp and that β-caryophyllene possessed the stronger binding affinity and higher inhibition potential calculated by MM-PBSA. Present findings strengthen our hypothesis about the potential chemosensitizing power of caryophyllane sesquiterpenes and suggest that combining a chemosensitizer and a metronomic schedule can represent a suitable strategy to overcome drawbacks of doxorubicin chemotherapy while exploiting its powerful activity.

P-glycoprotein Expressing-B cell associated Active True Renal Lupus Vasculitis in Lupus Nephritis

True renal lupus vasculitis (TRLV), a rare form of vascular lesion usually associated with proliferative lupus nephritis (LN), is resistant to conventional treatments and associated with poor renal outcome among renal vasculopathies. Evidence suggests the involvement of P-glycoprotein (P-gp) expressing-activated B cells in the pathogenesis and treatment resistance of TRLV through the production of autoantibodies and direct infiltration into the inflammatory lesion of small vessels. Therapies targeting activated B cells might overcome refractory TRLV. Identification of the subsets of peripheral activated B cells that express P-gp in TRLV patients might help the selection of suitable treatment strategy.

P-glycoprotein: a role in the export of amyloid-β in Alzheimer's disease?

The accumulation of amyloid-β (Aβ) peptides is a key histopathological feature of the Alzheimer's brain. Defective clearance mechanisms result in toxic levels of soluble Aβ40 and Aβ42 oligomers, leading to impaired synaptic function, neurodegeneration and cognitive decline. Growing evidence points to the involvement of P-glycoprotein (P-gp or ABCB1), an ATP-binding cassette transporter highly expressed on the luminal side of the blood-brain barrier, in facilitating the clearance of Aβ from the brain. In this review, we summarise evidence from human, animal and invitro studies examining the contribution of P-gp to Aβ clearance, and discuss the potential for P-gp as a novel pharmacological target in Alzheimer's disease (AD). P-gp expression and activity in the brain are inversely correlated with ageing, Aβ deposition and AD. Moreover, Aβ itself has been found to compromise the expression of P-gp, thereby exacerbating Aβ deposition and disease. Despite decades of research, the pathophysiology of AD remains elusive. Understanding the normal versus impaired processing and clearance mechanisms affecting Aβ peptides will assist the development of more effective therapeutic agents to combat this progressive neurodegenerative condition that continues to devastate millions of patients globally.

Gait analysis in children with Fragile X Syndrome: could this become a measurable outcome?

The multikinase inhibitor regorafenib, which is a standard treatment for certain cancer patients after disease progression following other approved therapies, exhibits delayed-onset dermal toxicity. Here, we aimed to clarify the mechanisms that contribute to the increased dermal exposure to active metabolite M-5 of regorafenib after repeated oral administration. The dermal concentration of M-5 at 24 h after the last 5 oral administrations of regorafenib in mdr1a/1b/bcrp-/- mice was more than 190 times that in wild-type mice. The skin-to-plasma concentration ratio of M-5 in mdr1a/1b/bcrp-/- was also higher than in wild-type mice, suggesting possible involvement of P-glycoprotein and breast cancer resistance protein in regulating the dermal distribution. The area under the plasma concentration-time curve values of M-5 and its precursor M-2 in plasma of mdr1a/1b/bcrp-/- were at most 26 and 3 times those in wild-type mice, respectively. Interestingly, repeated administration of regorafenib markedly increased the area under the plasma concentration-time curve of M-5 in plasma, but not liver, compared with a single dose. Intravenous administration of M-5 dose-dependently reduced the liver-to-plasma concentration ratio. Our results indicate that hepatic uptake of M-5 may partially explain the accumulation of M-5 in the systemic circulation, but multiple factors, including influx and efflux transporters, are involved in determining dermal exposure to M-5.

Downregulation of ABCB1 gene in patients with total hip or knee arthroplasty influences pharmacokinetics of rivaroxaban: a population pharmacokinetic-pharmacodynamic study.

Rivaroxaban is a substrate for ABCB1 transporter and is commonly used in patients undergoing hip or knee replacement surgery for thromboprophylaxis. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the influence of ABCB1 gene expression and polymorphism on rivaroxaban exposure and anticoagulation effects. Five blood samples per patient were collected during 5days after the surgery for the determination of rivaroxaban concentration in plasma and for determination of prothrombin time and partial thromboplastin time. Non-linear mixed effects model was used for a population PK-PD analysis and for testing covariate effects. A one-compartment PK model with first-order absorption adequately described the pharmacokinetic data. The typical oral clearance (CL/F) was 6.12L/h (relative standard error, 15.8%) and was associated with ABCB1 expression. Compared to base line before the surgery, a significant ABCB1 downregulation was observed 5days after the surgery (p < 0.001). Prothrombin time and partial thromboplastin time were both linearly associated to the logarithm of the rivaroxaban plasma concentration. We confirmed that variable rivaroxaban CL/F is associated with ABCB1 expression, which is in accordance with previous studies on P-glycoprotein involvement in rivaroxaban PK. Furthermore, we observed the downregulation of ABCB1 expression after the surgery. The cause remains unclear and further research is needed to explain the underlying mechanisms.

Influx and Efflux Transporters Contribute to the Increased Dermal Exposure to Active Metabolite of Regorafenib After Repeated Oral Administration in Mice

The multikinase inhibitor regorafenib, which is a standard treatment for certain cancer patients after disease progression following other approved therapies, exhibits delayed-onset dermal toxicity. Here, we aimed to clarify the mechanisms that contribute to the increased dermal exposure to active metabolite M-5 of regorafenib after repeated oral administration. The dermal concentration of M-5 at 24 h after the last 5 oral administrations of regorafenib in mdr1a/1b/bcrp-/- mice was more than 190 times that in wild-type mice. The skin-to-plasma concentration ratio of M-5 in mdr1a/1b/bcrp-/- was also higher than in wild-type mice, suggesting possible involvement of P-glycoprotein and breast cancer resistance protein in regulating the dermal distribution. The area under the plasma concentration-time curve values of M-5 and its precursor M-2 in plasma of mdr1a/1b/bcrp-/- were at most 26 and 3 times those in wild-type mice, respectively. Interestingly, repeated administration of regorafenib markedly increased the area under the plasma concentration-time curve of M-5 in plasma, but not liver, compared with a single dose. Intravenous administration of M-5 dose-dependently reduced the liver-to-plasma concentration ratio. Our results indicate that hepatic uptake of M-5 may partially explain the accumulation of M-5 in the systemic circulation, but multiple factors, including influx and efflux transporters, are involved in determining dermal exposure to M-5.

Involvement of the Transporters P-Glycoprotein and Breast Cancer Resistance Protein in Dermal Distribution of the Multikinase Inhibitor Regorafenib and Its Active Metabolites

Regorafenib is a multikinase inhibitor orally administered to colorectal cancer patients, and is known to often exhibit dermal toxicity. The purpose of this study is to clarify possible involvement of P-glycoprotein and breast cancer resistance protein (BCRP) in the dermal accumulation of regorafenib and its active metabolites M-2 and M-5. Following intravenous administration in triple knockout (Abcb1a/1b/bcrp−/−; TKO) and wild-type (WT) mice, delayed plasma clearance of M-2 and M-5, but not regorafenib, was observed in TKO mice compared to WT mice. Elacridar, an inhibitor of both transporters, also caused delayed clearance of M-2 and M-5, suggesting that these transporters are involved in their elimination. Skin-to-plasma concentration ratios of regorafenib, M-2, and M-5 were significantly higher in TKO mice than in WT mice. Elacridar increased skin-to-plasma and epidermis-to-plasma concentration ratios of regorafenib. Basal-to-apical transport of M-2 and M-5 was observed in LLC-PK1-Pgp and MDCKII/BCRP/PDZK1 cells, which was inhibited by elacridar and the BCRP inhibitor Ko143, respectively. The present findings thus indicate that P-glycoprotein and BCRP are involved in the accumulation of regorafenib and its active metabolites in the skin, by affecting either their systemic exposure or their plasma distribution in the circulating blood.

Involvement of P-glycoprotein and multidrug and toxin extrusion protein 1 in hepatic and renal berberine efflux in mice

Involvement of P-glycoprotein (P-gp) and multidrug and toxin extrusion protein 1 (MATE1) in the hepatic and renal efflux of berberine was identified using transfected cells, a mouse model, and molecular docking.

Role of Human Breast Cancer Related Protein versus P-Glycoprotein as an Efflux Transporter for Benzylpenicillin: Potential Importance at the Blood-Brain Barrier.

While the blood-brain barrier (BBB) protects the brain by controlling the access of solutes and toxic substances to brain, it also limits drug entry to treat central nervous system disorders. Many drugs are substrates for ATP-binding cassette (ABC) transporters at the BBB that limit their entry into the brain. The role of those transporters in limiting the entry of the widely prescribed therapeutic, benzylpenicillin, has produced conflicting results. This study investigated the possible potential involvement of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), two ABC transporters, in benzylpenicillin transport at BBB in human using MDCKII cells overexpressing those transporters as well as pharmacological inhibition. MDCKII cells overexpressing human BCRP (MDCKII-BCRP) but not those overexpressing human P-gp (MDCKII-MDR cells) had reduced [3H]benzylpenicillin uptake. Similarly, inhibiting BCRP increased [3H]benzylpenicillin uptake in MDCKII-BCRP cells, while inhibiting P-gp in MDCKII-MDR cells had no effect on uptake although there was evidence that benzylpenicillin is a substrate for canine P-gp. While inhibiting BCRP affected [3H]benzylpenicillin cell concentrations it did not affect transepithelial flux in MDCKII-BCRP cells. In summary, the results indicate that human BCRP and not human P-gp is involved in benzylpenicillin transport. However, targeting BCRP alone was not sufficient to alter transepithelial flux in MDCKII cells. Whether it would be sufficient to alter blood-to-brain flux at the human BBB remains to be investigated.

Evidence for P-Glycoprotein Involvement in Cell Volume Regulation Using Coulter Sizing in Flow Cytometry.

The regulation of cell volume is an essential function that is coupled to a variety of physiological processes such as receptor recycling, excitability and contraction, cell proliferation, migration, and programmed cell death. Under stress, cells undergo emergency swelling and respond to such a phenomenon with a regulatory volume decrease (RVD) where they release cellular ions, and other osmolytes as well as a concomitant loss of water. The link between P-glycoprotein, a transmembrane transporter, and cell volume regulation is controversial, and changes in cells volume are measured using microscopy or electrophysiology. For instance, by using the patch-clamp method, our team demonstrated that chloride currents activated in the RVD were more intense and rapid in a breast cancer cell line overexpressing the P-glycoprotein (P-gp). The Cell Lab Quanta SC is a flow cytometry system that simultaneously measures electronic volume, side scatter and three fluorescent colors; altogether this provides unsurpassed population resolution and accurate cell counting. Therefore, here we propose a novel method to follow cellular volume. By using the Coulter-type channel of the cytometer Cell Lab Quanta SC MPL (multi-platform loading), we demonstrated a role for the P-gp during different osmotic treatments, but also a differential activity of the P-gp through the cell cycle. Altogether, our data strongly suggests a role of P-gp in cell volume regulation.

Preclinical Pharmacokinetics and In Vitro Metabolism of BMS-605339: A Novel HCV NS3 Protease Inhibitor

BMS-605339 is a potent HCV NS3 protease inhibitor that suppresses hepatitis C virus replication and was under investigation as an oral agent for the treatment of this disease. In vitro and in vivo studies were conducted in mouse, rat, dog, and monkey to characterize the pharmacokinetics and metabolism of this compound. BMS-605339 was predicted to be a moderate clearance compound in the human, based on human microsomal and hepatocyte data. Nearly all metabolism of BMS-605339 was oxidative; CYP3A4 is likely to play a key role in the metabolic clearance of this compound. Moderate to high Caco-2 permeability was observed for this compound, with the potential for P-glycoprotein involvement. The oral bioavailability of BMS-605339 was variable and dose dependent, suggesting low absorption, possibly because of transporter involvement. BMS-605339 possesses low intrinsic aqueous solubility and, in both rat and dog, administration of an aqueous suspension suggested that BMS-605339 absorption is likely solubility limited. Liver exposure of BMS-605339 was consistently higher than plasma exposure in all species tested (mouse, rat, and dog), indicating the potential for active uptake into hepatocytes. The overall preclinical pharmacokinetic profile supported the selection and development of BMS-605339 as a clinical candidate.

Methotrexate-bestatin interaction: Involvement of P-glycoprotein and organic anion transporters in rats

To clarify the pharmacokinetic interaction and its possible mechanism, mutual effects between methotrexate (MTX) and bestatin in oral absorption and renal excretion in rats were examined in vivo and in vitro. A sensitive, quick and high performance method (LC-MS/MS) was used to determine concentrations of MTX and bestatin in biological samples. Plasma concentrations of MTX and bestatin markedly increased following oral and intravenous administration of MTX in combination with bestatin. The cumulative urinary excretion and renal clearance of the two drugs significantly decreased when MTX and bestatin were co-administered intravenously. Uptake of the two drugs in in situ single-pass intestinal perfusion studies and in vitro everted intestinal sac preparations significantly increased when co-administered, while uptake in rat kidney slices and hOAT1- or hOAT3-HEK 293 cells significantly decreased. Transport rates of bestatin and MTX from basolateral-to-apical transepithelial transport in MDR1-MDCK cells significantly decreased following co-administration. Additionally, intracellular concentrations increased, and the efflux transport of the two drugs was inhibited when given together. The IC₅₀ values of MTX and bestatin in K562 and K562/ADR cells decreased when the two were co-administered. These findings indicate that the pharmacokinetic mechanism of interaction between MTX and bestatin occurs through co-transport by P-gp in the intestinal mucosa and OATs within the kidneys.

Assessment of the Roles of P-glycoprotein and Cytochrome P450 in Triptolide-induced Liver Toxicity in Sandwich-Cultured Rat Hepatocyte Model

Triptolide (TP), a main bioactive component of Tripterygium wilfordii Hook F., is a promising agent for treatment of autoimmune diseases. However, a high incidence of dose-limiting hepatotoxicity was observed in the clinic. Sandwich-cultured rat hepatocyte model was used in this study to identify the involvement of P-glycoprotein (P-gp) in TP disposition and to evaluate TP-induced hepatotoxicity after modulation of P-gp by the known inhibitors, ritonavir and tariquidar, and known inducers, phenobarbital, quercetin, and H(2)O(2). Our data showed that biliary clearance of TP reduced 73.7% and 84.2% upon treatment of ritonavir (25 µM) and tariquidar (5 µM), respectively. In contrast, increases of 346%, 280%, and 273% in biliary clearance of TP were observed with treatment of phenobarbital (1.0 mM), quercetin (20 µM), and H(2)O(2) (0.5 mM), respectively. The TP-induced hepatotoxicity increased by twofold when CYP activity was blocked by 1-aminobenzotriazole, suggesting that CYP and P-gp may both contribute to the detoxification of TP in the SCRH model. In addition, hepatotoxicity and the expression of apoptosis proteins Bax and Bcl-2 were correlated qualitatively with the TP exposure duration and its intracellular concentration, which, in turn, can be modulated by P-gp inhibitors or inducers. Our results for the first time demonstrated that in addition to CYP-mediated metabolism, P-gp also plays an important role in the disposition of TP and TP-induced hepatotoxicity. Thus, the modulation of canalicular P-gp has a potential to cause drug-drug interaction between TP and the coadministered P-gp inhibitors or inducers in the clinic.

Capsaicin pretreatment increased the bioavailability of cyclosporin in rats: Involvement of P-glycoprotein and CYP 3A inhibition

Capsaicin (CAP), the main ingredient responsible for the hot pungent taste of chilli peppers. This study investigated the effect of CAP on the pharmacokinetics of Cyclosporin A (CyA) in rats and the mechanism of this food-drug interaction. The results indicated that after 7 days of low or middle dose of CAP (0.3 or 1.0 mg/kg), the blood concentration of CyA was not significantly changed compared with that of vehicle-treated rats, whereas the blood concentration of CyA in high dose group (3.0 mg/kg) was significantly increased. The total clearance (CL/F) of CyA was decreased, and the bioavailability was significantly increased to about 1.44-fold of that in vehicle-treated rats after 7 days of high dose CAP treatment. At this time, the P-gp and CYP3A1/2 in the liver and intestine were decreased at both the mRNA and protein levels. These results demonstrated that chronic ingestion of high doses of CAP will increase the bioavailability of CyA to a significant extent in rats and the food-drug interaction between CAP and CyA appears to be due to modulation of P-gp and CYP3A gene expression by CAP, with differential dose-dependence.

Effects of Itraconazole, Dexamethasone and Naringin on the Pharmacokinetics of Nadolol in Rats

The aim of the present study was to clarify the involvement of P-glycoprotein (P-gp) or organic anion transporting polypeptide (Oatp) 1a5 in the pharmacokinetics of nadolol (NDL), a non-metabolized hydrophilic β-adrenoceptor blocker, in rats. Pretreatment with itraconazole (ICZ, P-gp inhibitor, 50 mg/kg) for 30 min before oral administration of NDL (10 mg/kg) significantly increased the area under the plasma concentration-time curve (AUC₀₋∞)of NDL by 1.7-fold compared with control. Intragastric administration of dexamethasone (DEX, 8 mg/kg) for 4 consecutive days increased P-gp level in the intestine and the liver. In line with this, DEX pre-treatment decreased maximum plasma concentration (C(max)) of NDL by 28% of control. To inhibit the intestinal Oatp1a5, naringin (NRG, 0.145 mg/kg) was preadministered orally for 30 min before the oral administrations of NDL or celiprolol (CEL, 10 mg/kg, Oatp1a5 substrate). Although NRG markedly reduced C(max) and AUC₀₋∞ of CEL by 60% and 65% of control, respectively, little difference was observed in the plasma concentration of NDL between NRG and control. These results suggest that P-gp is greatly involved in the pharmacokinetics of NDL, while the involvement of Oatp1a5 in the pharmacokinetics of NDL may be less than that of celiprolol in rats.