UGT Enzymes Research Articles

Reduction in N-Desmethylclozapine Level Is Determined by Daily Dose But Not Serum Concentration of Valproic Acid-Indications of a Presystemic Interaction Mechanism.

Valproic acid (VPA) is frequently used together with clozapine (CLZ) as mood-stabilizer or for the prevention of seizures in patients with psychotic disorders. VPA is known to reduce levels of the pharmacologically active CLZ-metabolite N-desmethylclozapine (N-DMC), but factors determining the degree of this interaction are unknown. Here, we investigated the relationship between VPA dose and serum concentration on N-DMC levels in a large patient population adjusting for sex, age, and smoking habits as covariates. A total of 763 patients with steady-state serum concentrations of CLZ and N-DMC concurrently using VPA (cases, n = 76) or no interacting drugs (controls, n = 687) were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital, Oslo, between March 2005 and December 2016. In addition to information about prescribed doses, age, sex, smoking habits, and use of other interacting drugs were obtained. The effects of VPA dose and serum concentration on dose-adjusted N-DMC levels were evaluated by univariate correlation and multivariate linear mixed-model analyses adjusting for covariates. The dose-adjusted N-DMC levels were approximately 38% lower in VPA users (cases) versus nonusers (controls) (P < 0.001). Within the VPA cases, a negatively correlation between VPA dose and dose-adjusted N-DMC levels was observed with an estimated reduction of 1.42% per 100-mg VPA dose (P = 0.033) after adjusting for sex, age, and smoking. By contrast, there was no correlation between VPA serum concentration and dose-adjusted N-DMC levels (P = 0.873). The study shows that VPA dose, not concentration, is of relevance for the degree of reduction in N-DMC level in clozapine-treated patients. Presystemic induction of UGT enzymes or efflux transporters might underlie the reduction in N-DMC level during concurrent use of VPA. Our findings indicate that a VPA daily dose of 1500 mg or higher provides a further 21% reduction in N-DMC concentration. This is likely a relevant change in the exposure of this active metabolite where low levels are associated with implications of CLZ therapy.

Prominent Stereoselectivity of NNAL Glucuronidation in Upper Aerodigestive Tract Tissues.

Tobacco specific nitrosamines (TSNAs) are among the most potent carcinogens found in cigarettes and smokeless tobacco products. Decreases in TSNA detoxification, particularly 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been associated with tobacco-related cancer incidence. NNK is metabolized by carbonyl reduction to its major carcinogenic metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is detoxified by glucuronidation at the nitrogen within the pyridine ring or at the chiral alcohol to form four glucuronide products: (R)-NNAL-O-Gluc, (S)-NNAL-O-Gluc, (R)-NNAL-N-Gluc, (S)-NNAL-N-Gluc. Stereoselective NNAL-Gluc formation and the relative expression of NNAL-glucuronidating UGTs (1A4, 1A9, 1A10, 2B7, 2B10, 2B17) were analyzed in 39 tissue specimens from the upper aerodigestive tract (esophagus (n = 13), floor of mouth (n = 4), larynx (n = 9), tongue (n = 7), and tonsil (n = 6)). All pooled tissue types preferentially formed (R)-NNAL-O-Gluc in the presence of racemic-NNAL; only esophagus exhibited any detectable formation of (S)-NNAL-O-Gluc. For every tissue type examined, UGT1A10 exhibited the highest relative expression levels among the NNAL-O-glucuronidating UGTs, ranging from 36% (tonsil) to 49% (esophagus), followed by UGT1A9 > UGT2B7 > UGT2B17. UGT1A10 also exhibited similar or higher levels of expression as compared to both NNAL-N-glucuronidating UGTs, 1A4 and 2B10. In a screening of cells expressing individual UGT enzymes, all NNAL glucuronidating UGTs exhibited some level of stereospecific preference for individual NNAL enantiomers, with UGTs 1A10 and 2B17 forming primarily (R)-NNAL-O-Gluc. These data suggest that UGTs 1A10 and 2B17 may be important enzymes in the detoxification of TSNAs like NNK in tissues of the upper aerodigestive tract.

Drug Interactions of Acetaminophen (Paracetamol) involving CYP and UGT Enzymes

Drug Interactions of Acetaminophen (Paracetamol) involving CYP and UGT Enzymes

Metabolism of Scoparone in Experimental Animals and Humans.

Scoparone, a major constituent of the Chinese herbal medicine Yin Chen Hao, expresses beneficial effects in experimental models of various diseases. The intrinsic doses and effects of scoparone are dependent on its metabolism, both in humans and animals. We evaluated in detail the metabolism of scoparone in human, mouse, rat, pig, dog, and rabbit liver microsomes in vitro and in humans in vivo. Oxidation of scoparone to isoscopoletin via 6-O-demethylation was the major metabolic pathway in liver microsomes from humans, mouse, rat, pig and dog, whereas 7-O-demethylation to scopoletin was the main reaction in rabbit. The scoparone oxidation rates in liver microsomes were 0.8 - 1.2 µmol/(min*g protein) in mouse, pig, and rabbit, 0.2 - 0.4 µmol/(min*g protein) in man and dog, and less than 0.1 µmol/(min*g) in rat. In liver microsomes of all species, isoscopoletin was oxidized to 3-[4-methoxy-ρ-(3, 6)-benzoquinone]-2-propenoate and esculetin, which was formed also in the oxidation of scopoletin. Human CYP2A13 exhibited the highest rate of isoscopoletin and scopoletin oxidation, followed by CYP1A1 and CYP1A2. Glucuronidation of isoscopoletin and scopoletin was catalyzed by the human UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, and UGT2B17. Dog was most similar to man in scoparone metabolism. Isoscopoletin glucuronide and sulfate conjugates were the major scoparone in vivo metabolites in humans, and they were completely excreted within 24 h in urine. Scoparone and its metabolites did not activate key nuclear receptors regulating CYP and UGT enzymes. These results outline comprehensively the metabolic pathways of scoparone in man and key preclinical animal species.

Tobacco smoking and its drug interactions with comedications involving CYP and UGT enzymes and nicotine

Tobacco smoking and its drug interactions with comedications involving CYP and UGT enzymes and nicotine

Drug Interactions of SGLT2 Inhibitors (Gliflozins) Involving UGT Enzymes

Drug Interactions of SGLT2 Inhibitors (Gliflozins) Involving UGT Enzymes

Use of generally recognized as safe or dietary compounds to inhibit buprenorphine metabolism: potential to improve buprenorphine oral bioavailability.

The present study evaluated the potential of five generally recognized as safe (GRAS) or dietary compounds (α-mangostin, chrysin, ginger extract, pterostilbene and silybin) to inhibit oxidative (CYP) and conjugative (UGT) metabolism using pooled human intestinal and liver microsomes. Buprenorphine was chosen as the model substrate as it is extensively metabolized by CYPs to norbuprenorphine and by UGTs to buprenorphine glucuronide. Chrysin, ginger extract, α-mangostin, pterostilbene and silybin were tested for their inhibition of the formation of norbuprenorphine or buprenorphine glucuronide in both intestinal and liver microsomes. Pterostilbene was the most potent inhibitor of norbuprenorphine formation in both intestinal and liver microsomes, with IC50 values of 1.3 and 0.8μM, respectively, while α-mangostin and silybin most potently inhibited buprenorphine glucuronide formation. The equipotent combination of pterostilbene and ginger extract additively inhibited both pathways in intestinal microsomes. Since pterostilbene and ginger extract showed potent CYP and/or UGT inhibition of buprenorphine metabolism, their equipotent combination was tested to assess the presence of synergistic inhibition. However, because the combination showed additive inhibition, it was not used while performing IVIVE analysis. Based on quantitative in vitro-in vivo extrapolation, pterostilbene (21mg oral dose) appeared to be most effective in improving the mean predicted Foral and AUC∞ PO of buprenorphine from 3±2% and 340±330ng*min/ml to 75±8% and 36,000±25,000ng*min/ml, respectively. At a 10-fold lower dose of pterostilbene, the predicted buprenorphine Foral approximated sublingual bioavailability (~35%) and showed a 2-4 fold reduction in the variability around the predicted AUC∞ PO of buprenorphine. These results demonstrate the feasibility of using various GRAS/dietary compounds to inhibit substantially the metabolism by CYP and UGT enzymes to achieve higher and less variable oral bioavailability. This inhibitor strategy may be useful for drugs suffering from low and variable oral bioavailability due to extensive presystemic oxidative and/or conjugative metabolism.

Characterization of the CYP and UGT enzymes involved in reactive metabolite generation from bromfenac and bromfenac indolinone

Characterization of the CYP and UGT enzymes involved in reactive metabolite generation from bromfenac and bromfenac indolinone

Chemical Probes for Human UDP‐Glucuronosyltransferases: A Comprehensive Review

UGTs play crucial roles in the metabolism and detoxification of both endogenous and xenobiotic compounds. The key roles of UGTs in human health have garnered great interest in the design and development of specific probes for human UGTs. However, in contrast to other human enzymes, the probe substrates for human UGTs are rarely reported, owing to the highly overlapping substrate specificities of UGTs and the lack of the integrated crystal structures of UGTs. Over the past decades, many efforts are made to develop specific probe substrates for UGTs and use them in both basic research and drug discovery. This review focuses on recent progress in the development of probe substrates for UGTs and their biomedical applications. A long list of chemical probes for UGTs, including non-fluorescent and fluorescent probes along with their structural information and kinetic parameters, are prepared and analyzed. Additionally, challenges and future directions in this field are highlighted in the final section. All information and knowledge presented in this review provide practical tools/methods for measuring UGT activities in complex biological samples, which will be very helpful for rapid screening and characterization of UGT modulators, and for exploring the relevance of UGT enzymes to human diseases.

Abstract 1912: A microbial glucuronidase target implicated in intestinal reactivation of tyrosine kinase inhibitors

Abstract Many drugs are inactivated by liver UGT enzymes and reactivated by enteric bacterial β-glucuronidases (GUS), an axis of drug metabolism that contributes to gut toxicities of anti-neoplastic agents, NSAIDs, and potentially other drug classes. For example, toxic reactivation of irinotecan by E. coli GUS is the causative event leading to intense, delayed diarrhea. Receptor tyrosine kinase (RTK)-targeted cancer drugs that undergo this UGT-GUS axis of metabolism are also associated with a high incidence of diarrhea. However, glucuronides of RTK inhibitors (RTKi) are not substrates of E. coli GUS. We recently reported that the human gut microbiome expresses nearly 300 distinct GUS enzymes (GUSome). The objective of this work is to identify the GUS enzyme(s) capable of metabolizing the glucuronide of the RTKi, sorafenib, that may contribute to sorafenib-induced diarrhea. We used UGT1A9 supersomes to make sorafenib-glucuronide (S-G) from commercially purchased sorafenib. S-G was screened against a library of 15 purified GUSome enzymes to identify the specific GUS orthologs that can cleave S-G, which was determined by monitoring sorafenib absorbance at 280 nm. Similar approaches were used to identify GUS enzymes that can cleave other RTKi's. Of the GUS enzymes evaluated for cleavage of S-G, only the GUS enzyme from an uncultured Eubacterium species was active. The structurally similar regorafenib-glucuronide and two glucuronides of other RTKi's (axitinib and imatinib) are also substrates of Eubacterium GUS. All four RTKi's are associated with diarrhea in at least 40-60% of patients. In contrast to E. coli GUS, very little is known about Eubacterium GUS. We have identified a set of RTKi-glucuronides as the first substrates of Eubacterium GUS, which may contribute to diarrhea associated with targeted anti-cancer drugs. Citation Format: Bret David Wallace, Jeffrey Hymes, Matthew Redinbo, Ward Peterson. A microbial glucuronidase target implicated in intestinal reactivation of tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1912.

The Effect of Piperine Pro-Nano Lipospheres on Direct Intestinal Phase II Metabolism: The Raloxifene Paradigm of Enhanced Oral Bioavailability.

Phase II biotransformation reactions have been gaining more attention due totheiracknowledged significance in drug bioavailability, drug development, and drug-drug interactions. However, the predominant role of phase I metabolism has always overshadowed phase II metabolism, resulting in insufficient data regarding its mechanisms. In this paper, we investigate the effect of an advanced lipid based formulationon the phase II metabolism process of glucuronidation, occuring in the enterocytes monolayer. The investigated formulation is a self-emulsifying drug delivery system, termed pro-nano lipospheres, which contains the natural absorption enhancer piperine. To evaluate the effect of this formulation on direct glucuronidation we chose the model molecule raloxifene. First, glucuronidation is the main clearance pathway of this compound without involvement of preceding mechanisms. Second, raloxifene's extensive glucuronidation site is primarily at the intestine. Raloxifene's oral bioavailability was determined in a series of pharmacokinetic experiments using the freely moving rat model. In order to test the effect of the formulation on the relevant UGT enzymes reported in the clinic, we used the in vitro method of UGT-GloAssay. Coadministration of raloxifene and piperine pro-nano lipospheres to rats resulted in a 2-fold increase in the relative oral bioavailability of raloxifene. However, coadministration of raloxifene with blank pro-nano lipospheres had no effect on its oral bioavailability. In contrast to the difference found in vivo between the two vehicles, both formulations extended an inhibitory effect on UGT enzymes in vitro. Ultimately, these findings prove the ability of the formulation to diminish intestinal direct phase II metabolism which serves as an absorption obstacle for many of today's marketed drugs. Pro-nano lipospheres is a formulation that serves as a platform for the simultaneous delivery of the absorption enhancer and a required drug. The discrepancy found between the in vivo and in vitro models demonstrates that the in vitro method may not be sensitive enough to distinguish the difference between the formulations.

Charactering the metabolism of cryptotanshinone by human P450 enzymes and uridine diphosphate glucuronosyltransferases in vitro.

Cryptotanshinone (CT) is the main active component in the root of Salvia miltiorrhiza Bunge (SMB) that displays antibacterial, anti-inflammatory and anticancer activities. In this study, we characterized phase I and phase II metabolism of CT in human liver microsomes in vitro and identified the metabolic enzymes (CYPs and UGTs) involved. The metabolites of CT generated by CYPs were detected using LC-MS/MS and the CYP subtypes involved in the metabolic reactions were identified using chemical inhibitors of CYP enzymes and recombinant human CYP enzymes (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Glucuronidation of CT was also examined, and the UGT subtypes involved in the metabolic reactions were identified using recombinant human UGT enzymes (1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15 and 2B17). After adding NADPH to the human liver microsomes incubation system, CT was transformed into 6 main dehydrogenation and hydroxylation metabolites. CYP2A6, CYP3A4 and CYP2C19 were the major contributors to the transformation of its hydroxylation metabolites. CYP2C19, CYP1A2 and CYP3A4 were the major contributors to the transformation of its hydrogenation metabolites in human liver microsomes. This study showed that the metabolites at m/z of 473 were mediated by UGT1A9 and that the metabolites at m/z of 489 were mediated by UGT2B7 and UGT2B4. CT was extensively metabolized by UGTs following metabolism by CYPs in the liver.

Fractional contribution of CYP and UGT enzymes to the disposition of cannabinoids

Fractional contribution of CYP and UGT enzymes to the disposition of cannabinoids

Reaction phenotyping for UGT enzymes

Reaction phenotyping for UGT enzymes

Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for valproic acid and divalproex

Valproic acid (VPA) is an older first-line antiepileptic drug with a complex pharmacokinetic (PK) profile, currently under investigation for several novel neurologic and non-neurologic indications. Our study objective was to design and validate a mechanistic model of VPA disposition in adults and children; and evaluate its predictive performance of drug-drug interactions (DDIs). This study expands upon existing physiologically based pharmacokinetic (PBPK) models for VPA by incorporating UGT enzyme kinetics and an advanced dissolution, absorption, and metabolism (ADAM) model for extended-release (ER) formulation. PBPK models for VPA IR and ER formulations were constructed using Simcyp Simulator (Version 15). First-order absorption was used for the immediate-release (IR) formulation and the ADAM model, including a controlled-release profile, for ER. Data from twenty-one published clinical studies were used to assess model performance. The model accurately predicted the concentration-time profiles of IR formulation for single-dose and steady-state doses ranging from 200mg to 1000mg. Similarly profiles were also simulated for ER formulation after a single-dose and steady-state doses of 500mg and 1000mg, respectively. In addition, simulated PK profiles agreed well with the observed data from studies in which VPA ER formulation was given to pediatric patients and VPA IR formulation to adult patients with cirrhosis. The model was further validated with individual adult data from a Phase I clinical trial consisting of eight cohorts after IV infusion of VPA with doses ranging from 15 to 150mg/kg. Co-administrations of VPA as an enzyme-inhibitor with victim drug phenytoin or lorazepam, as well as a substrate with enzyme inducer carbamazepine or phenobarbital, were simulated with the model to evaluate drug-drug interaction. The simulated serum concentration-time profiles were within the 5th and 95th percentiles, and the majority of the predicted area-under-the-curve (AUC) and peak plasma concentration (Cmax) values were within 25% of the reported average values. The comprehensive VPA PBPK model defined by this study may be used to support dosage regimen optimization to improve the safety and efficacy profile of this agent under different scenarios.

Identification of human cytochrome P450 and UGT enzymes involved in the metabolism of ferulic acid, a major bioactive component in traditional Chinese medicines

Ferulic acid (FA) is an active component of herbal medicines. One of the best documented activities of FA is its antioxidant property. Moreover, FA exerts antiallergic, anti-inflammatory, and hepatoprotective effects. However, the metabolic pathways of FA in humans remain unclear. To identify whether human CYP or UGT enzymes are involved in the metabolism of FA, reaction phenotyping of FA was conducted using major CYP-selective chemical inhibitors together with individual CYP and UGT Supersomes. The CYP- and/or UGT-mediated metabolism kinetics were examined simultaneously or individually. Relative activity factor and total normalized rate approaches were used to assess the relative contributions of each major human CYPs towards the FA metabolism. Incubations of FA with human liver microsomes (HLM) displayed NADPH- and UDPGA-dependent metabolism with multiple CYP and UGT isoforms involved. CYPs and UGTs contributed equally to the metabolism of FA in HLM. Although CYP1A2 and CYP3A4 appeared to be the major contributors in the CYP-mediated clearance, their contributions to the overall clearance are still minor (< 25%). As a constitute of many food and herbs, FA poses low drug-drug interaction risk when co-administrated with other herbs or conventional medicines because multiple phase I and phase II enzymes are involved in its metabolism.

Inhibitory Effects of Selected Antituberculosis Drugs on Common Human Hepatic Cytochrome P450 and UDP-glucuronosyltransferase Enzymes.

The comorbidities of tuberculosis and diseases such as HIV require long-term treatment with multiple medications. Despite substantial in vitro and in vivo information on effects of rifampicin and isoniazid on human CYPs, there is limited published data regarding the inhibitory effects of other anti-TB drugs on human CYPs and UGTs. The inhibitory effects of five first-line anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and rifabutin), and the newly approved bedaquiline, were evaluated for six common human hepatic UGT enzymes (UGT1A1, 1A4, 1A6, 1A9, 2B7 and 2B15) in vitro using HLMs. Pyrazinamide, ethambutol, rifabutin and bedaquiline were also studied for their inhibitory effects on eight of the most common human CYP enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). Rifabutin inhibited multiple CYPs to varying degrees in vitro, but with all IC50 values exceeding 25 µM. Rifabutin and rifampicin also inhibited several human UGTs including UGT1A4. The Ki value for rifabutin on human hepatic UGT1A4 was 2 μM. Finally, the six anti-TB drugs produced minimal inhibition of acetaminophen glucuronidation in vitro. Overall, the findings do not raise major concerns regarding metabolic inhibition of human hepatic CYPs and UGTs by the tested anti-TB drugs.

Menthol exhibits stereospecific inhibition of phase II UGT enzymes

Mint flavoring (menthol) is often included as a flavor additive with many consumer products including candy, toothpaste and medications as well as various brands of tobacco. Menthol is a chiral aliphatic alcohol, with each enantiomer called D‐ or L‐menthol and the racemic mixture being referred to as DL‐menthol. Menthol can be added to tobacco products as either L‐menthol or DL‐menthol in both menthol and certain non‐menthol tobacco cigarette brands. Tobacco‐specific nitrosamines (TSNAs) are among the most potent carcinogens found in tobacco, and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) is the most potent and one of the most abundant. NNK is extensively metabolized to the equally carcinogenic chiral 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanol (NNAL). (S)‐NNAL exhibits higher stereoselective tissue retention in mice and humans and has been shown to be more carcinogenic in mice than its counterpart (R)‐NNAL. NNAL is primarily detoxified by six UDP‐glucuronyltransferase (UGT) enzymes [UGTs: 1A4, 1A9, 1A10, 2B7, 2B10 and 2B17]; each of these UGTs have been shown to have different stereospecificity for the formation of one NNAL glucuronide (NNAL‐gluc) over the other. DL‐Menthol has been shown to inhibit NNAL‐gluc formation in human liver microsomes. This differential carcinogenic potential and stereospecific metabolism makes it increasingly important to know which UGT enzymes are being inhibited by each of the menthol enantiomers. The goal of the present studies was to examine differences in the glucuronidation of menthol enantiomers and the inhibitory effects of these enantiomers on the glucuronidation of NNAL. Menthol exhibits the strongest inhibition of NNAL‐gluc formation for UGT2B7 with L‐ and D‐menthol exhibiting similar IC50 values of ~100 μM. This is in strong contrast to UGT1A9, where each menthol enantiomer exhibits a significantly (p &lt; 0.001) different IC50 value, with D‐menthol exhibiting an IC50 (~1400 μM) that was more than double that of L‐menthol (~600 μM). For UGT2B7, there was a significant (p &lt; 0.05) difference between the L‐ and D‐menthol inhibition effect for the formation of (R)‐NNAL‐gluc, with IC50's ~100 μM and &gt;2500 μM, respectively, but no inhibition difference was observed for the formation of (S)‐NNAL‐gluc. These data indicate that the different menthol enantiomers could have a significant and stereospecific effect on the clearance of the tobacco carcinogen, NNAL in vivo.

Influence of age and co-medication on the steady-state pharmacokinetics of valproic acid in Tunisian patients with epilepsy

AimValproic acid (VPA) is a widely prescribed broad-spectrum antiepileptic drug. However, the use of VPA is complicated in clinical practice by its remarkably wide variability of pharmacokinetics. The objective of this study was to investigate the effects of demographic factors and associated therapies on steady-state plasma VPA concentrations in patients with epilepsy. MethodsThis retrospective cohort study was carried out using the routine therapeutic drug monitoring (TDM) database. Stepwise logistic regression analysis was used to compare serum VPA levels in 78 epilepsy patients treated with VPA in association with at least one other drug that could have interacted with CYP2C9, CYP2C19 or UGT enzymes. ResultsThe frequency of subtherapeutic serum VPA levels was significantly increased with younger age (P<0.02), the number of co-medications (P<0.007) and use of enzyme-inducing co-medications (P<0.02). No significant correlations between VPA dose and trough plasma concentrations were found, as the latter did not increase in proportion to the dose. ConclusionRoutine monitoring of VPA serum levels would be extremely useful in epilepsy patients in the pediatric age group and in those who require associated enzyme-inducing medications.

Investigation of Need of Natural Bioenhancer for a Metabolism Susceptible Drug-Raloxifene, in a Designed Self-Emulsifying Drug Delivery System.

Bioenhancers can increase the bioavailability of metabolism susceptible drugs. The present study was designed to understand the impact of bioenhancer on permeability and bioavailability of a biopharmaceutical drug disposition classification system (BDDCS) class II drug raloxifene (RLX). RLX undergoes extensive first pass metabolism by UGT enzymes in gastrointestinal tract (GIT) and has an oral bioavailability of about 2%. Self-emulsifying drug delivery system (SEDDS) of RLX was developed using a designed approach and this formulation was loaded with reported bioenhancers: quercetin and piperine. These formulations were tested for improvement in permeability and bioavailability of the RLX. The apparent permeability using everted gut sac (P app) for SEDDS (5.26 ± 1.10 × 10-8cm/s) was found to be similar to that of SEDDS with bioenhancers (5.11 ± 1.05 × 10-8cm/s). In oral bioavailability study in rat, SEDDS demonstrated a 4-fold and 2.5-fold higher AUC0-∞ than RLX suspension (control) and marketed product, respectively. No additional improvement in permeability and bioavailability was offered by inclusion of piperine and quercetin (bioenhancers) in the SEDDS.