Extensive Hepatic First-pass Metabolism Research Articles

Developments in managing severe chronic pain: role of oxycodone-naloxone extended release.

Chronic pain is a highly disabling condition, which can significantly reduce patients’ quality of life. Prevalence of moderate and severe chronic pain is high in the general population, and it increases significantly in patients with advanced cancer and older than 65 years. Guidelines for the management of chronic pain recommend opioids for the treatment of moderate-to-severe pain in patients whose pain is not responsive to initial therapies with paracetamol and/or nonsteroidal anti-inflammatory drugs. Despite their analgesic efficacy being well recognized, adverse events can affect daily functioning and patient quality of life. Opioid-induced constipation (OIC) occurs in 40% of opioid-treated patients. Laxatives are the most common drugs used to prevent and treat OIC. Laxatives do not address the underlying mechanisms of OIC; for this reason, they are not really effective in OIC treatment. Naloxone is an opioid receptor antagonist with low systemic bioavailability. When administered orally, naloxone antagonizes the opioid receptors in the gut wall, while its extensive first-pass hepatic metabolism ensures the lack of antagonist influence on the central-mediated analgesic effect of the opioids. A prolonged-release formulation consisting of oxycodone and naloxone in a 2:1 ratio was developed trying to reduce the incidence of OIC maintaining the analgesic effect compared with use of the sole oxycodone. This review includes evidence related to use of oxycodone and naloxone in the long-term management of chronic non-cancer pain and OIC.

Duodenum-triggered delivery of pravastatin sodium via enteric surface-coated nanovesicular spanlastic dispersions: Development, characterization and pharmacokinetic assessments

Pravastatin sodium (PVS) is a hydrophilic HMG-CoA reductase inhibitor that is mainly absorbed from duodenum. PVS has a short elimination half-life (1–3h), suffers from instability at gastric pH, extensive hepatic first-pass metabolism and low absolute bioavailability (18%). The current work aimed to develop enteric surface-coated spanlastic dispersions as controlled-release duodenum-triggered systems able to surmount PVS drawbacks. PVS-loaded spanlastic dispersions were prepared by ethanol-injection method using span® 60. Tween® 60 and Tween® 80 were explored as edge activators. As a novel approach, the fine spanlastic dispersions were surface-coated with an enteric-polymer (Eudragit® L100-55) via freeze-drying. The systems were evaluated, before and after enteric-coating, for particle size, zeta potential, PVS entrapment efficiency (EE%), morphology and PVS release studies. PVS pharmacokinetics from the best achieved system and an aqueous solution were estimated in rats by UPLC–MS/MS. The best achieved enteric surface-coated spanlastic dispersion (E-S6) displayed spherical nanosized vesicles (647.60nm) possessing negative zeta potential (−6.93mV), promising EE% (63.22%) and a biphasic drug-release pattern characterized by a retarded-release phase (0.1N HCl, 2h) and a controlled-release phase (pH 6.8, 10h). The higher Cmax, delayed Tmax, prolonged MRT(0−∞), longer elimination t50% and enhanced oral bioavailability unravel E-S6 potential for oral PVS delivery.

Budesonide for maintenance of remission in Crohn's disease.

Budesonide for maintenance of remission in Crohn's disease.

Down the hatch: is prescribing medication really that simple?

Drug absorption and metabolism is influenced by age, sex, pharmacogenetic variability, medical comorbidity, concurrent drug use, drug formulation, and route of administration. Drug dissolution typically begins in the stomach, but absorption occurs mainly in the small intestine. Malabsorption syndromes, previous gastrointestinal (GI) surgery, or decreased GI blood flow impair or delay the absorption of orally administered drugs. Decreased drug absorption can occur with certain gastric bypass procedures when the stomach or proximal small intestine is an important absorption site. Drugs undergoing extensive first-pass hepatic metabolism can have increased concentrations and greater systemic effects when administered directly into the jejunum. Non-oral routes of drug administration ordinarily bypass first-pass hepatic metabolism, leading to greater bioavailability and higher concentrations compared with oral administration of the same dose. Metabolic activity is variably reduced with increased age or liver disease severity, but declines in liver function cannot be quantified to determine drug metabolizing capacity.

Intestinal Lymphatic Delivery of Praziquantel by Solid Lipid Nanoparticles: Formulation Design,In VitroandIn VivoStudies

The aim of the present work was to design and develop Praziquantal (PZQ) loaded solid lipid nanoparticles (PZQ-SLN) to improve the oral bioavailability by targeting intestinal lymphatic system. PZQ is practically insoluble in water and exhibits extensive hepatic first-pass metabolism. PZQ SLN were composed of triglycerides, lecithin and various aqueous surfactants; were optimized using hot homogenization followed by ultrasonication method. The optimized SLN had particle size of123±3.41 nm, EE of86.6±5.72%. The drug release of PZQ-SLN showed initial burst release followed by the sustained release. Inspite of zeta potential being around −10 mV, the optimized SLN were stable at storage conditions (5±3°C and25±2°C/60±5% RH) for six months. TEM study confirmed the almost spherical shape similar to the control formulations. Solid state characterization using differential scanning calorimeter (DSC) and powder X-ray diffraction (PXRD) analysis confirmed the homogeneous distribution of PZQ within the lipid matrix. The 5.81-fold increase inAUC0→∞, after intraduodenal administration of PZQ-SLN in rats treated with saline in comparison to rats treated with cycloheximide (a blocker of intestinal lymphatic pathway), confirmed its intestinal lymphatic delivery. The experimental results indicate that SLN may offer a promising strategy for improving the therapeutic efficacy and reducing the dose.

First-pass Metabolism of Decursin, a Bioactive Compound of Angelica gigas, in Rats

Decursin is considered the major bioactive compound of Angelica gigas roots, a popular Oriental herb and dietary supplement. In this study, the pharmacokinetics of decursin and its active metabolite, decursinol, were evaluated after the administration of decursin in rats. The plasma concentration of decursin decreased rapidly, with an initial half-life of 0.05 h. It was not detectable at 1 h after intravenous administration at an area under the plasma concentration-time curve of 1.20 µg · mL-1·h, whereas the concentration of decursinol increased rapidly reaching a maximum concentration of 2.48 µg · mL-1 at the time to maximum plasma concentration of 0.25 h and an area under the plasma concentration-time curve of 5.23 µg · mL-1·h. Interestingly, after oral administration of decursin, only decursinol was present in plasma, suggesting an extensive hepatic first-pass metabolism of decursin. The extremely low bioavailability of decursin after its administration via the hepatic portal vein (the fraction of dose escaping first-pass elimination in the liver, FH = 0.11) is indicative of extensive hepatic first-pass metabolism of decursin, which was confirmed by a tissue distribution study. These findings suggest that decursin is not directly associated with the bioactivity of A.gigas and that it may work as a type of natural prodrug of decursinol.

The long‐term efficacy and safety of a testosterone mucoadhesive buccal tablet in testosterone‐deficient men

What's known on the subject? and What does the study add? Striant® SR is the only available buccal delivery system for testosterone replacement therapy. Previous pharmacokinetic studies have shown that Striant SR effectively produces physiological serum testosterone levels in hypogonadal men. Efficacy and safety data from previously unpublished studies over 2 years of continuous use indicate that Striant SR is effective long term in maintaining serum testosterone within a physiological range, is well tolerated and has a high level of patient acceptance. Striant® sustained-release (SR) is a mucoadhesive buccal tablet (30 mg testosterone, The Urology Company) that adheres to the gum surface in the mouth providing controlled- and sustained-release of testosterone over a 12-h dosing period, offering a unique and rational method of testosterone delivery. Striant SR is indicated for testosterone-replacement therapy (TRT) for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests. Pharmacokinetic studies have shown that testosterone is released from Striant SR in a manner similar to the normal daily rhythm of endogenous testosterone secretion, with serum levels rising rapidly after insertion and peak levels reached by the second 12-hourly dose with no accumulation over time. In clinical trials involving hypogonadal men receiving Striant SR for up to 2 years, mean serum testosterone levels have always remained within the normal range. Striant SR is well tolerated, with gum-related disorders (such as irritation, inflammation and gingivitis) and taste perversion being the most commonly reported adverse events, reported by 5.6-16.3% and 3.0-4.1% of patients, respectively. Once patients have become accustomed to it, Striant SR has a high level of patient acceptance. In a long-term study, 90% of patients rated the twice-daily dosing as acceptable, just under half preferred it to other forms of TRT that they have used and 96% found it to be cosmetically acceptable. There is no clinically significant risk of testosterone transfer from Striant SR, as any testosterone that may be present in the saliva when swallowed is subject to extensive first-pass hepatic metabolism. It is pertinent to note that the saliva of eugonadal men contains similar levels of endogenous testosterone. Buccal delivery is particularly suitable where easy and rapid reversal of treatment might be required (such as in late-onset hypogonadism) and where there is a need to avoid the potential for transfer of testosterone to women and young children.

Effects of Kaempferol, an Antioxidant, on the Bioavailability and Pharmacokinetics of Nimodipine in Rats

The aim of this study was to investigate the effects of kaempferol on the pharmacokinetics of nimodipine in rats. Nimodipine and kaempferol interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in kaempferol being taken concomitantly with nimodipine as a combination therapy to treat orprevent cardiovascular disease. The effect of kaempferol on P-gp and CYP3A4 activity was evaluated and Pharmacokinetic parameters of nimodipine were determined in rats after an oral (12 mg/kg) and intravenous (3 mg/kg) administration of nimodipine to rats in the presence and absence of kaempferol (0.5, 2.5, and 10 mg/kg). Kaempferol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration (IC50) of 17.1 µM. In addition, kaempferol significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ ADR cells overexpressing P-gp. Compared to the oral control group, the area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of nimodipine significantly increased, respectively. Consequently, the absolute bioavailability of nimodipine in the presence of kaempferol (2.5 and 10 mg/kg) was 29.1-33.3%, which was sig- nificantly enhanced compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.30- to 1.49-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine was not affected by kaempferol in contrast to those of oral nimodipine. Kaempferol significantly enhanced the oral bioavailability of nimo- dipine, which might be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and /or in the liver and to inhibition of the P-gp efflux transporter in the small intestine by kaempferol. The increase in oral bioavailability of nimodipine in the presence of kaempferol should be taken into consideration of potential drug interactions between nimodipine and kaempferol. Key wordsNimodipine, Kaempferol, Pharmacokinetics, Bioavailability, P-gp, CYP3A4, Rats Nimodipine is a dihydropyridine calcium channel blocker that has been shown to selectively dilate cerebral arteries and increase cerebral blood flow in animals and humans (Kazda et al., 1982). Its major therapeutic indication is for the prevention and treatment of delayed ischemic neurological disorders that often occur in patients with subarachnoid hemorrhages (Epstein and Loutzenhister, 1990; Scholz, 1997). Nimodipine is rapidly absorbed after oral administration and is widely dis- tributed throughout the body. Orally administered nimodipine is subject to an extensive first-pass hepatic metabolism from the portal circulation, resulting in a low systemic bioavail- ability (Maruhn et al., 1985; Suwelack et al., 1985). Usually only the parent compound is active and most of the metabolic steps involve reactions catalyzed by cytochrome P450 (CYP) enzymes. CYP enzymes have been shown to catalyze pyridine

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.

Ketamine*

Ketamine*

Formulation and characterization of lipid-based drug delivery system of raloxifene-microemulsion and self-microemulsifying drug delivery system.

Background:Raloxifene, a second-generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women is administered orally in the form of a tablet. The absolute bioavailability of the drug is only 2% because of extensive hepatic first-pass metabolism. Lipid-based formulations are reported to reduce the first-pass metabolism by promoting its lymphatic uptake.Materials and Methods:In the present investigation, microemulsion and Self-Microemulsifying Drug Delivery System (SMEDDS) formulations of Raloxifene were prepared. The prepared formulations were characterized for drug loading, size, transparency, zeta potential, Transmission Electron Microscopy (TEM) and in vitro intestinal permeability.Results:The results indicated that high drug loading, optimum size and desired zeta potential and transparency could be achieved with both SMEDDS and microemulsion. The TEM studies indicated the absence of aggregation with both the systems. The in vitro intestinal permeability results showed that the permeation of the drug from the microemulsion and SMEDDs was significantly higher than that obtained from the drug dispersion and marketed formulation.Conclusion:Lipid based formulations such as microemulsion and Self Microemulsifying drug delivery systems are expected to increase the oral bioavailability as evidenced by the increased intestinal permeation.

Drug-Induced Arrhythmia

Prolongation of the QTc interval has been associated with proarrhythmia resulting from a potentially fatal form of polymorphic ventricular tachycardia called torsades de pointes (TdP). Genetic forms of the long-QT syndrome (LQTS) associated with high arrhythmic risk have been causally related to mutations in ion channels responsible for the cardiac action potential; genetic factors associated with milder degrees of QTc prolongation and arrhythmic risk have also been described. Acquired forms of QTc prolongation and proarrhythmia, particularly related to drug therapy, are frequently related to drug effects on the same ion channels involved in genetic forms of LQTS. As is true for genetic forms of LQTS, there is a wide spectrum of potential drug effects on the QTc interval ranging from trivial to potentially lethal. Drug-induced QTc prolongation is a complicated phenomenon related not just to the properties or dose of a particular drug but also to drug-drug interactions and a variety of patient factors, including age, gender, the presence and severity of underlying heart disease, and genetic predisposition. Additionally, drug effects on other ion channels, including blockade of sodium channels (causing prolongation of the QRS interval rather than the QTc interval), are an important cause of drug-induced proarrhythmia. The purpose of this review is to summarize the available data related to acquired forms of LQTS, with particular focus on drug-related LQTS and proarrhythmia. A brief summary is presented here of genetic LQTS because the relevant genes and proteins form the basis for an understanding of the causes of acquired LQTS, and in any given patient, the QTc is determined by genetic, substrate, and environmental factors. Emphasis is placed on practical strategies for clinicians, with the goal of minimizing the risk of dangerous proarrhythmia related to the use of both cardiac and noncardiac drugs with the potential for QTc prolongation. Genetic …

Oral bioavailability enhancement of vinpocetine using self-microemulsifying drug delivery system containing long chain triglycerides: Preparation and in vitro/in vivo evaluation

Vinpocetine, a widely used neurotropic agent, has low oral bioavailability due to its poor solubility and extensive hepatic first-pass metabolism. In the present work, self-microemulsifying drug delivery systems (SMEDDS) employing long chain triglycerides (LCT) were successfully developed to increase vinpocetine’s solubility and reduce its hepatic first pass metabolism, thus enhancing its overall oral bioavailability. Maisine™35-1 was chosen as the lipid component in the formulated SMEDDS as it showed the maximal vinpocetine solubility within different LCT tested. Feasibility of obtaining SMEDDS, containing Maisine™35-1, together with Transcutol®HP and either Cremophor®EL or Tween 80, was evaluated using ternary phase diagrams. In vitro release studies performed in phosphate buffer of pH 7.4 illustrated that extent of vinpocetine release from SMEDDS was drastically higher than that obtained from commercial Cavinton® tablets. The industrial usefulness of the developed SMEDDS was evaluated regarding their m...

Enantioselective capillary electrophoresis for identification and characterization of human cytochrome P450 enzymes which metabolize ketamine and norketamine in vitro

Ketamine, a phencyclidine derivative, is used for induction of anesthesia, as an anesthetic drug for short term surgical interventions and in subanesthetic doses for postoperative pain relief. Ketamine undergoes extensive hepatic first-pass metabolism. Enantioselective capillary electrophoresis with multiple isomer sulfated β-cyclodextrin as chiral selector was used to identify cytochrome P450 enzymes involved in hepatic ketamine and norketamine biotransformation in vitro. The N-demethylation of ketamine to norketamine and subsequently the biotransformation of norketamine to other metabolites were studied via analysis of alkaline extracts of in vitro incubations of racemic ketamine and racemic norketamine with nine recombinantly expressed human cytochrome P450 enzymes and human liver microsomes. Norketamine was formed by CYP3A4, CYP2C19, CYP2B6, CYP2A6, CYP2D6 and CYP2C9, whereas CYP2B6 and CYP2A6 were identified to be the only enzymes which enable the hydroxylation of norketamine. The latter two enzymes produced metabolic patterns similar to those found in incubations with human liver microsomes. The kinetic data of ketamine N-demethylation with CYP3A4 and CYP2B6 were best described with the Michaelis–Menten model and the Hill equation, respectively. This is the first study elucidating the individual enzymes responsible for hydroxylation of norketamine. The obtained data suggest that in vitro biotransformation of ketamine and norketamine is stereoselective.

In vitro Intestinal Absorption and First-pass Intestinal and Hepatic Metabolism of Cycloastragenol, a Potent Small Molecule Telomerase Activator

Cycloastragenol (CAG) is the aglycone derivative of astragaloside IV which has recently been demonstrated to activate telomerase and represents a potential drug candidate for the treatment of degenerative diseases. In the present study, intestinal absorption and metabolism of CAG were examined using the Caco-2 model and liver microsomes, respectively. The results showed that CAG rapidly passes through the Caco-2 cell monolayer by passive diffusion. Four different glucuronide conjugates and two oxidized CAG metabolites were found in the apical and basolateral sides of Caco-2 monolayer, suggesting that first-pass intestinal metabolism of CAG might occur upon passage through the intestinal epithelium. CAG underwent extensive metabolism in rat and human liver microsomes with only 17.4% and 8.2%, respectively, of the starting amount of CAG remaining after 30 min of incubation. Monohydroxylation of the parent and oxidization of the hydroxylated CAG were found in the liver samples. The present study indicates that CAG is efficiently absorbed through intestinal epithelium. However, extensive first-pass hepatic metabolism would limit the oral bioavailability of this compound.

Preparation and In Vitro/In Vivo Characterization of Porous Sublingual Tablets Containing Ternary Kneaded Solid System of Vinpocetine with β-Cyclodextrin and Hydroxy Acid

The demand for sublingual tablets has been growing during the previous decades especially for drugs with extensive hepatic first-pass metabolism. Vinpocetine, a widely used neurotropic agent, has low oral bioavailability due to its poor aqueous solubility and marked first-pass metabolism. Accordingly, the aim of this work was to develop tablets for the sublingual delivery of vinpocetine. Initially, the feasibility of improving vinpocetine’s poor aqueous solubility by preparing kneaded solid systems of the drug with β-Cyclodextrin and hydroxy acids (citric acid and tartaric acid) was assessed. The solid system with improved solubility and dissolution properties was incorporated into porous tablets that rapidly disintegrate permitting fast release of vinpocetine into the sublingual cavity. The pores were induced into these tablets by directly compressing the tablets’ excipients with a sublimable material, either camphor or menthol, which was eventually sublimated leaving pores. The obtained results demonstrated that the tablets prepared using camphor attained sufficient mechanical strength for practical use together with rapid disintegration and dissolution. In vivo absorption study performed in rabbits indicated that the sublingual administration of the proposed porous tablets containing vinpocetine solid system with β-Cyclodextrin and tartaric acid could be useful for therapeutic application.

The Relationship between the Drug Concentration Profiles in Plasma and the Drug Doses in the Colon

After the dosing of an extended-release (ER) formulation, compounds may exist in solutions at various concentrations in the colon because the drugs are released at various speeds from the ER dosage form. The aim of this study was to investigate the relationship between the drug concentration profiles in plasma and the drug doses in the colon. Several drug solutions of different concentrations were directly administered into the ascending colon of dogs using a lubricated endoscope, and the effects of the drug dose on colonic absorption were estimated. As a result, dose-dependency of colonic absorption varied from compound to compound. Although the relative bioavailability of colonic administration of diclofenac, metformin and cevimeline compared to oral administration was similar regardless of the drug doses in the colon, colonic absorption of diltiazem varied according to the doses. From the results of the co-administration of verapamil and fexofenadine, it was clear that diltiazem underwent extensive hepatic and gastrointestinal first-pass metabolism, resulting in a low area under the curves (AUC) at a low drug dose. During the design of oral ER delivery systems, a colonic absorption study of candidate compounds should be carried out at several solutions of different drug concentrations and assessed carefully.

Design and In Vitro Evaluation of a Novel Vaginal Drug Delivery System Based on Gelucire

Carbamazepine indicated for the control of epilepsy, undergoes extensive hepatic first-pass metabolism after oral administration. A vaginal dosage form of carbamazepine is not commercially available. Conventional suppository having poor retention in the vaginal tract, as they are removed in a short time by the tract's self-cleansing action, having poor patient compliance. To overcome such problems, delivery system with mucoadhesive polymers polyox WSR N-60K and Ucarflock 302 that prolong drug permanence on the vaginal mucosa were developed. In the present study the suitability of gelucires to formulate vaginal pesseries was investigated. The possible modification of carbamazepine release kinetics by using gelucires blends and hydrophilic additives in the pesseries was evaluated. It was observed that among gelucire grades melting point higher than 37 degrees C, the release rate proved to be highly dependant on HLB value and matrix composition. In most of the formulations carbamazepine release occurred by disintegration and erosion of the matrices which is depending upon the vehicle employed. The aging study revealed that the formulations containing G50/13 and G50/13-G44/14 blends undergo some changes during one year of shelf aging. From the results obtained it can be concluded that different gelucire grades and their blends along with hydrophilic polymer could be successesively used to formulate prolong release carbamazepine pesseries.

Formulation, evaluation, and comparison of bilayered and multilayered mucoadhesive buccal devices of propranolol hydrochloride

The purpose of this research work was to establish mucoadhesive buccal devices of propranolol hydrochloride (PRH) in the forms of bilayered and multilayered tablets. The tablets were prepared using sodium carboxymethylcellulose (SCMC) and Carbopol-934 (CP) as bioadhesive polymers to impart mucoadhesion and ethyl cellulose (EC) to act as an impermeable backing layer. Buccal devices were evaluated by different parameters such as weight uniformity, content uniformity, thickness, hardness, surface pH, swelling index, ex vivo mucoadhesive strength, ex vivo mucoadhesion time, in vitro drug release, and in vitro drug permeation. As compared with bilayered tablets, multilayered tablets showed slow release rate of drug with improved ex vivo bioadhesive strength and enhanced ex vivo mucoadhesion time. The mechanism of drug release was found to be non-Fickian diffusion (value of n between 0.5 and 1.0) for both the buccal devices. The stability of drug in both the optimized buccal devices was tested for 6 hours in natural human saliva; both the buccal devices were found to be stable in natural human saliva. The present study concludes that mucoadhesive buccal devices of PRH can be a good way to bypass the extensive hepatic first-pass metabolism and to improve the bioavailability of PRH.

Oral budesonide in the management of Crohn's disease.

To review the pharmacology, pharmacokinetics, efficacy, and safety of oral budesonide (Entocort EC) in the treatment of mild to moderate Crohn's disease (CD). The MEDLINE database (1966-December 2002) was searched using the key words budesonide and inflammatory bowel diseases and restricted to the English language. The references from relevant articles were also reviewed for additional citations. Articles and abstracts that evaluated oral budesonide for management of CD were considered, with emphasis on randomized, controlled clinical trials. Budesonide's high potency at the glucocorticoid receptor and extensive first-pass hepatic metabolism result in a topical antiinflammatory effect on intestinal tissue, with minimal systemic glucocorticoid adverse effects. Clinical trials have demonstrated that budesonide is effective in the treatment of patients with mild to moderate CD of the ileum and ascending colon, with efficacy similar to prednisolone and superior to mesalamine. Long-term therapy with budesonide increased the duration of CD remission, but the effect was not sustained up to 1 year. Budesonide failed to prevent postsurgical relapse of CD. Adrenal suppression and glucocorticoid-related adverse effects have been reported at lower rates in patients treated with budesonide compared with prednisolone. Patients prescribed budesonide should be monitored for hepatic dysfunction and potential drug interactions. Budesonide is an effective and relatively safe option for treatment of mild to moderate CD of the ileum and ascending colon.