XenoPort is a biopharmaceutical company focused on developing a portfolio of internally discovered product candidates for the potential treatment of central nervous system (CNS) disorders and gastroesophageal reflux disease (GERD). The company's drug discovery efforts focus on utilizing the body's natural nutrient transporter mechanisms to improve the therapeutic benefits of drugs. The most advanced product candidate is being developed for the potential treatment of restless legs syndrome (RLS) and the management of neuropathic pain. The company's goal is to develop orally available, patentable new chemical entity that addresses large potential markets using currently marketed drugs that have deficiencies in the oral absorption, distribution and/or metabolism. XenoPort's new candidate, called a Transported Prodrug, is created by modifying the chemical structure of the currently marketed parent drug. XenoPort scientists have designed these Transported Prodrugs to be actively transported from the gastrointestinal, or GI, tract into the bloodstream, where they are metabolized to release the parent drug.
A key component of the company's strategy is to reduce the risks and time associated with drug development by capitalizing on the known safety, efficacy, and established drug development history of the parent drugs. In addition, XenoPort's improved prodrug products are designed to be metabolized to release the parent drugs and natural substances with favorable safety characteristics. This strategy aims to increase the probability of successfully development, as well as potentially expanding the indication for which the parent drugs have not been approved, but are nevertheless used off-label after having demonstrated efficacy in clinical trials. The company is located in Santa Clara, CA and employs approximately 150 professionals.
XenoPort's scientists had identified specific high-capacity nutrient transporter proteins found in cells that line the gastrointestinal (GI) tract. The company then chemically alters existing pharmaceutical products to take advantage of these active transport proteins to improve absorption into the bloodstream. XenoPort identifies existing pharmaceutical products that address large potential markets, but have failed to achieve peak penetration because of deficiencies in the oral absorption, distribution and/or metabolism. The newly improved, patentable, Transported Prodrug utilizes the body's own natural mechanisms for actively transporting nutrients through cellular barriers. Once in the blood stream, these Transported Prodrugs are engineered to split apart, releasing the active drug and natural substances.
Source: http:// www. xenoport. com/corporate/transpop.html
XenoPort currently has two clinical stage product candidates and three pre-clinical stage candidates:
The company's most advanced clinical stage candidate is XP-13512, a Transported Prodrug of gabapentin. Gabapentin, originally developed by Pfizer, came to market in 1993 under the brand name Neurontin. Neurontin is approved for the management of post-herpetic neuralgia (PHN) and for the treatment of partial seizures. It is often prescribed by doctors to treat other neuropathic pain conditions, such as painful diabetic neuropathy, and is considered by many to be the gold standard for the treatment of neuropathic pain. Worldwide sales of Neurontin in 2004 were $2.7 billion ($2.2 billion in the U.S.). In late 2004, Pfizer's exclusivity on gabapentin expired.
Despite its commercial success, XenoPort believes that gabapentin therapy can be substantially improved. Studies have shown that as many as 70% of post-herpetic neuralgia patients do not respond to gabapentin therapy. Gabapentin absorption after oral administration is highly variable among patients, and there is a ceiling on the amount of gabapentin that can be absorbed due to a limitation of the absorption mechanism of the drug. XenoPort believes the limited and variable absorption of gabapentin contributes to lack of efficacy in some patients. In addition, gabapentin's short half-life requires that it be administered three or four times a day, which may lead to poor compliance and reduced efficacy in some patients. Attempts to develop sustained-release formulations of gabapentin have failed because the drug is poorly absorbed in the colon, where sustained-release systems reside for the majority of time in their transit through the intestine.
Management believes that XP-13512 addresses the deficiencies of gabapentin by targeting high-capacity nutrient transporter mechanisms expressed throughout the length of the intestines. Theoretically, this approach can overcome the variable and suboptimal exposure to gabapentin experienced by patients. In addition, by targeting transporters expressed throughout the length of the intestines, the company has been able to develop a sustained-release (SR) tablet formulation of XP-13512 that overcomes the need for frequent dosing of gabapentin. XP-13512 is designed to rapidly convert to gabapentin once absorbed from the GI tract, resulting in limited systemic exposure to the intact Transported Prodrug. In addition to producing gabapentin, XP-13512 is metabolized to release other components such as CO2, acetaldehyde, and isobutyrate all well-studied compounds with no serious safety issues.
XenoPort conduced a phase I clinical trials in healthy volunteers to demonstrate that, in contrast to gabapentin, oral administration of XP-13512 produces dose-proportional blood levels of gabapentin across a broad range of doses. Additional phase I trials with a sustained-release formulation of XP-13512 have demonstrated that, compared to equivalent doses of gabapentin, XP-13512 produced higher levels of gabapentin in the blood for a longer period of time. XP-13512 was well tolerated in all clinical trials at all doses tested with no serious adverse events. In total there were 16 phase I safety and tolerability programs for XP-13512. XenoPort dosed as high as 6000mg and found no serious adverse reactions. This is 5x the expected therapeutic dose. Based on this data, management initiated and has since completed a four phase II clinical programs of XP-13512 for the treatment of Restless Leg Syndrome (RLS) and post-herpetic neuralgia (PHN). This trial showed favorable results compared with both placebo and gabapentin, which is widely used to treat PHN / neuropathic pain.
Phase IIa data demonstrated 1200mg of XP-13512 prior to bedtime significantly improved total sleep time (TST), slow wave sleep (SWS), Wake After Sleep Onset (WASO), and two measures of waking (PLMSW) and arousal (PLMSA) caused by RLS during the course of the night. In a phase IIb trial XenoPort demonstrated that XP-13512 reduced the baseline IRLS (international restless leg syndrome-scale) by 16.1 points (22.4 to 6.3) after two weeks vs. 8.9 points (22.4 to 13.5) for the placebo. This was highly significant and compares well to other RLS drugs such as Boehringer's Mirapex and Glaxo's Requip. XP-13512 also had approximately 81.2% of the patients (vs. 48.5% for placebo) show a significant improvement in RLS signs and symptoms. This data suggest superiority to either Mirapex or Requip.
Management initiated a multi-trial, large-scale, phase III program in RLS in March 2006. The trial is intended to provide safety and efficacy data to support the filing and approval of a New Drug Application (NDA) for XP-13512 as a treatment for RLS. There are a total of four phase III programs designed to demonstrate efficacy and confirm long-term safety for the NDA filing. The trials are outlined below:
Study XP052 ( A randomized, double-blind, placebo-controlled trial that was designed to evaluate the safety and efficacy of 1200 mg of XP-13512 administered once a day for 12 weeks in 222 patients with moderate-to-severe primary RLS. This trial was fully enrolled in October 2006 and top-line results from April 2007 are presented below:
Study XP053 ( A randomized, double-blind, placebo-controlled trial intended to evaluate the safety and efficacy of 600mg and 1200mg of XP-13512 administered once a day for 12 weeks. The inclusion of a 600mg dosing group in this trial will enable an evaluation of the effectiveness of this dose after 12 weeks of treatment and is expected to provide useful information for studying the pharmacokinetic/pharmacodynamic relationship for XP13512 in RLS. A dose of 600mg of XP13512 was not effective after two weeks of testing in RLS patients in XenoPort's prior phase IIb clinical trial. This trial recently completed enrollment at 315 patients. Treatment should wrap-up shortly, with data is expected in the first quarter 2008.
The co-primary outcome measures for Studies XP052 and XP053 are defined to be the change from baseline in the International Restless Legs Syndrome (IRLS) rating scale and the Clinical Global Impression (CGI) of Improvement at the end of treatment. Secondary endpoints include onset of efficacy and subjective sleep, pain, mood and quality of life assessments. XenoPort has enrolled patients from the XP052 and XP053 studies into an open-label expansion program called XT-55. This data will constitute a third phase III trial to be submitted to the FDA in 2008.
Study XP060 ( A placebo-controlled, "randomized withdrawal" design intended to evaluate the long-term efficacy of XP-13512 to evaluate relapse of RLS symptoms in XP-13512-treated or placebo-treated patients who had previously achieved clinical improvement while taking 1200 mg of XP-13512 for 24 weeks in 300 patients. The goal of the study is to assess the clinical remission of patients once taken off XP-13512. XenoPort completed this study in January 2007 and data is expected early 2008.
There will also be a definitive QTc study, a driving study, and a more extensive pharmacokinetic study to support exposure response data. The company will also complete an ongoing two year mouse and rat carcinogenicity study as part of the NDA package. All of this data, combined with those from four phase III XP-13512 clinical trials, are intended to meet the International Committee for Harmonization (ICH) guidelines for safety assessment. Based on the top-line data from the -052 trial, XP-13512 looks clean. There were no serious adverse events (SAE) seen in the -052 study, only an increase in somnolence (26.5% vs. 7.4%) and dizziness (19.5% vs. 4.6%). Neither of these are of great concern, although we will be keeping an eye on the driving study to see if next-day hangover effects or the somnolence issue causes a problem for patients.
On February 8, 2007 XenoPort announced that it has formed an exclusive agreement to co-develop and commercialize XP-13512 in the U.S. and other countries outside of Asia and Japan with GlaxoSmithKline. XenoPort had previously licensed the drug to Astellas for sale in Japan and certain Asian countries. Astellas is in phase II trials in Japan. Under the terms of the agreement with Glaxo, XenoPort received (in March 2007) an up-front cash payment of $75 million. XenoPort is also eligible to receive aggregate milestone payments of up to $65 million for development activities leading up to the NDA filing for RLS, up to $210 million in other potential development and regulatory milestone payments and up to $290 million in potential sales milestone payments based on successful commercialization of XP-13512 for RLS and neuropathic pain. In this regard, Glaxo paid XenoPort $10 million in April 2007 based on the top-line -052 data and $11 million shortly after for completion of the trial. Plus, in addition to royalties on sales outside the U.S., XenoPort is entitled to receive tiered, double-digit royalty payments on U.S. sales of XP-13512 unless XenoPort elects to co-promote the drug with Glaxo in the U.S., in which case it will be entitled to participate in a net profit share. If XenoPort decides to co-promote XP-13512 in the U.S., it is also entitled to detail Requip products currently in development by Glaxo, provided they are approved in the U.S. These follow-on Requip products could include a 14-hour once daily product, and a 24-hour controlled-release product specifically designed for the Parkinson's disease market.
In the U.S., XenoPort will complete the ongoing studies to support RLS development. Subject to positive phase III clinical data, Glaxo will file the NDA for RLS for FDA approval. We expect the filing to take place during the second half of 2008. Glaxo will lead development and registration for all other indications, including neuropathic pain. The neuropathic pain market is significantly larger than the RLS market, but competition is also more intense. Pfizer's Lyrica and Lilly s Cymbalta have gained sizable market share in this category. Previous data on XP-13512 in neuropathic pain is encouraging but we are holding off on modeling sales until we see more data. Glaxo will initiate multiple phase II trials in 2008. As will Astellas in Japan. Glaxo will also be solely responsible for the manufacture of XP-13512 to support its development and commercialization within the licensed territories. XenoPort is currently in the process of transferring manufacturing "know-how" to Glaxo so that the companies can be in position to include this validation with the NDA package and prepare for the commercial launch.
At this time we expected XenoPort to move forward with the potential co-promote / joint venture route in the U.S. This affords management the opportunity to build its own specialty sales force which it could eventually use to promote other internally-developed candidates such as XP-19986 or XP-21279 we discuss below.
Glaxo is currently a major player in the RLS market with Requip. Requip was originally approved for the treatment of Parkinson's Disease but has seen sales surge in the past several quarters thanks to expansion into RLS. Requip sales grew 74% in 2006 to 268 million ($495 million). Sales in the second quarter were $165 million, up 41%. Based on superior efficacy and a cleaner safety profile, XenoPort's XP-13512 could potentially post worldwide sales far beyond that level. Requip is currently priced around $1.80 per pill. We think that XP-13512 could be priced as high as $3 per pill based on improved characteristics. Sales in the U.S. could approach $400-500 million alone. We currently model a launch by Glaxo in 2009 with XenoPort co-promoting the drug along with Requip 14-hour or 24-hour. We expect Glaxo to use their existing Requip sales force. Requip will lose patent protection in May 2008 (with a six-month extension). By the time XP-13512 launches the Requip sales force will be ready and hungry to promote the new product. XP-13512 is patent protected to at least 2022.
We assume a joint-venture model with XenoPort recoding net JV losses in 2008 and 2009, with JV profits in 2010 and beyond. Outside the U.S. XenoPort will receive a royalty on sales from Glaxo and Astellas in their select territories.
XenoPort's second clinical candidate is XP-19986, a Transported Prodrug of the "R" isomer of baclofen. Baclofen is a muscle relaxant and anti-spasticity agent that was originally approved in 1977 to ease the symptoms of spasticity in patients with multiple sclerosis (MS) and spinal cord injury (SCI). Although baclofen has acceptable oral bioavailability, its short plasma half-life necessitates dosing three to four times per day. This dosing regimen can produce substantial peaks and troughs in a patient's exposure to the drug, which may result in significant side effects such as drowsiness, weakness and dizziness during peak drug level, and diminished efficacy during trough blood levels. Because baclofen is poorly absorbed in the colon, it cannot be effectively administered via a sustained-release dosage form since sustained-release systems act primarily through absorption of drug in the lower GI tract. XenoPort is developing several sustained-release versions of XP-19986 to be studied in the phase II trials expected to start year end 2007.
XP-19986 is designed to overcome the deficiencies of baclofen by targeting high-capacity nutrient transporter mechanisms expressed throughout the length of the entire GI tract, including the colon. By targeting these transporters, XenoPort believes that XP-19986 can be formulated in a sustained-release pill and thereby require less frequent dosing than generic baclofen. Moreover, XP-19986 produces only the "R" isomer of baclofen, known as R-baclofen, while generic baclofen is racemic containing a 50:50 mixture of the "R (active) and "S" (inactive) isomers. Theories exist that S-baclofen may even have antagonistic characteristics, so a pure R-baclofen compound may be highly efficacious as lower doses. This could provide for improved efficacy and greater tolerability.
Baclofen is an acknowledged market leader in spasticity with over 3 million prescriptions annually. However, recent studies have indicated that baclofen may also be effective in treating gastro-esophageal reflux disease (GERD). XenoPort management believes that many patients develop GERD by inappropriate relaxation of the sphincter muscle that separates the stomach and esophagus, allowing stomach contents to enter the esophagus. Current approved drugs that treat GERD, such as proton pump inhibitors and H2 antagonists, reduce the acidity of stomach contents, thereby reducing the symptoms of GERD, especially heartburn. By contrast, XP-19986 has the potential to reduce the inappropriate relaxation of the lower esophageal sphincter, and thereby reduce the reflux itself. As such, XP-19986 may successfully treat symptoms associated with reflux of non-acidic stomach contents, for which proton pump inhibitors and H2 antagonists are ineffective.
In September 2007 management released data from a phase I trial designed to assess the safety, tolerability and pharmacokinetics of the SR3 formulation of XP19986 dosed once (QD) or twice (BID) daily in healthy adult volunteers.
The trial demonstrated sustained levels of XP19986 over 24 hours and enabled identification of suitable doses for further clinical studies of XP19986. More specifically, the trial demonstrated that repeated QD dosing of XP19986 resulted in sustained levels of R-baclofen in blood over 24-hours, which reached steady-state within three days. The phase I clinical trial also indicated that XP19986 was well tolerated under the tested conditions. All reported adverse effects were consistent with those previously reported for racemic baclofen.
The early work with regard to efficacy in GERD looks encouraging. Patients on XP-19986 have demonstrated a sustained reduction in events that reached significance out as far as 10 hours post meal consumption. The 40mg and 60mg doses also resulted in a reduction in the number of cases of heartburn associated with a reflux episode over the 12-hour monitoring period.
XenoPort plans to initiate a two phase II clinical trials on XP19986 before year end 2007. The first trial will enroll roughly 150 patients with GERD and test the SR3 formulation with doses of 20, 40, 60mg 1x daily and 30mg 2x daily.
The second trial will enroll roughly 36 patients with spasticity and test the SR1 formulation with doses 10, 20, 30mg 2x daily. We are excited about the potential for this drug. Clearly the positive top-line results from the -052 study with XP-13512 increases our enthusiasm that the "Transported Prodrug" technology works. XP-19986 is another potential hundred-million dollar idea that adds upside to the already strong XenoPort story.
XP-21279 is a Transported Prodrug of levodopa, or L-Dopa, one of the most effective therapies for reducing symptoms associated with Parkinson's disease, particularly in patients with severe Parkinson's disease. In spite of some improvements in L-Dopa therapy through co-administration of drugs designed to slow L-Dopa metabolism, the treatment remains suboptimal due to fluctuations in L-Dopa blood concentrations between doses. To date, a satisfactory sustained-release formulation of L-Dopa has not been possible due to poor colonic absorption.
In this regard, XP-21279 is designed to be well absorbed from the lower GI tract, thus it can be formulated for sustained release and improve upon the limiting factors of currently used L-Dopa. XenoPort is currently conducting preclinical studies with XP-21279 with an IND planned for the fourth quarter 2007. Management plans to initiate a phase I program before year end look at the pharmacokinetics of XP-21279 vs. generic levodopa.
XP-20925 is a Transported Prodrug of propofol, an intravenous anesthetic that is widely used in hospitals and outpatient settings to induce and maintain anesthesia during surgery, or to sedate patients undergoing diagnostic or medical procedures. Propofol was introduced in the United States in 1989 and is currently the world's leading IV anesthetic agent. Because propofol has very low oral bioavailability (due to its metabolism in the GI tract), it must be administered intravenously, limiting its uses to those procedures performed in hospital settings. Recent studies, however, have demonstrated that sub-anesthetic IV doses of propofol are effective in treating disorders such as nausea and vomiting and intractable migraine. Worldwide sales of anti-emetics for chemotherapy-induced nausea and for treatments of migraine each exceed $2 billion annually.
XenoPort believes that XP-20925 may be able to consistently achieve sub-anesthetic levels of propofol after oral dosing and may provide new methods for treating these disorders, especially for those patients who do not respond to current therapy. The drug is designed to utilize intestinal transporters to enhance absorption and simultaneously protect propofol from metabolism during absorption. Once absorbed, XP-20295 is designed to convert rapidly to propofol, resulting in therapeutic exposure to the drug. Initial animal studies have demonstrated excellent oral bioavailability of propofol from XP-20925.
Development plans for XP-20925 are currently on the backburner while XenoPort focuses on XP-13512 and XP-19986. However, future development plans could move forward as resources become available. Management may be in position to file an IND application in 2008.
In October 2007 XenoPort entered into an exclusive license agreement with Xanodyne Pharmaceuticals, Inc. for the development and commercialization in the U.S. of a preclinical, non-hormonal, oral Transported Prodrug product candidate, XP21510, for the potential treatment of women diagnosed with menorrhagia, or heavy menstrual bleeding. Under the terms of the agreement, XenoPort is entitled to receive cash payments totaling $12.0 million, of which $6.0 million was paid upon execution of the agreement and the remaining $6.0 million of which is due in October 2008. XenoPort is eligible to receive aggregate cash payments of up to $130.0 million and $5.0 million for XP21510 and XP12B, Xanodyne's phase III tranexamic acid product candidate, respectively, upon the achievement of certain development, regulatory and commercial milestones. In addition, XenoPort is entitled to receive tiered double-digit royalty payments on potential future sales of XP-21510, as well as escalating single-digit royalties on potential future sales of XP-12B. Xanodyne Pharmaceuticals represents an excellent collaboration partner for XenoPort considering the company's current work with XP-12B, a sustained-release formulation of tranexamic acid, and their in-house sales staff of approximately 100 representatives focusing on the OB/GYN market. We currently do not include royalties from the sale of XP-12B in our financial model, so this represents upside in the future.
About Restless Legs Syndrome, or RLS Restless legs syndrome is a common, under-diagnosed neurological disorder that frequently manifests itself as a sleep disorder. Patients who suffer from RLS experience an irresistible urge to move their legs. This urge is usually accompanied by unpleasant sensations of burning, creeping, tugging or tingling inside the patients' legs, ranging in severity from uncomfortable to painful. These RLS-related symptoms typically begin or worsen during periods of rest or inactivity, particularly when lying down or sitting, and may be temporarily relieved by movement such as walking or massaging the legs. Symptoms often worsen at night, and disturbed sleep is a common result of RLS. Left untreated, RLS may cause exhaustion, daytime fatigue, inability to concentrate and impaired memory. Although the exact prevalence rate of RLS is uncertain, a recent study has indicated that approximately 10% of patients visiting primary care physicians in five industrialized Western countries experience RLS symptoms at least weekly, with approximately 2% of patients visiting primary care physicians having symptoms severe enough to disrupt their quality of life.
About Neuropathic Pain
Neuropathy often results in numbness, abnormal sensations called dysesthesias and allodynias that occur either spontaneously or in reaction to external stimuli, and a characteristic form of pain, called neuropathic pain or neuralgia, that is qualitatively different from the ordinary nociceptive pain one might experience from stubbing a toe or hitting a finger with a hammer.
Neuropathic pain is usually perceived as a steady burning and/or "pins and needles" and/or "electric shock" sensations. The difference is due to the fact that "ordinary" pain stimulates only pain nerves, while a neuropathy often results in the firing of both pain and non-pain (touch, warm, cool) sensory nerves in the same area, producing signals that the spinal cord and brain do not normally expect to receive. Neuropathic pain is often caused by an illness such as diabetes, cancer, shingles, or the toxic effects of chemotherapy used to treat cancer or HIV. The current classes of drugs used to treat patients with neuropathic pain include anticonvulsants, antidepressants and opioids. Anticonvulsants represent the largest share of the neuropathic pain market, with gabapentin leading the class.
GERD is a digestive system disorder characterized by the frequent, undesirable passage of stomach contents into the esophagus that results in discomfort and potential damage to the lining of the esophagus. More than $10 billion is spent worldwide each year on GERD and heartburn medications, and approximately 7% of the global population experiences GERD symptoms daily. Conventional treatment for GERD includes medications that suppress stomach acid, such as proton pump inhibitors and H2-receptor antagonists, as well as over-the-counter antacids. However, these treatments are not effective in all patients, and there is a subset of patients who suffer from GERD symptoms due to reflux of stomach contents that are not acidic.
Menorrhagia is abnormally heavy and prolonged menstrual periods at regular intervals. While a normal menses cycle lasts 21 to 35 days with an average of five days of bleeding and total blood flow between 25 and 80 milliliters (mL), women with menorrhagia can have seven or more days of bleeding and lose more than 80 mL of blood per menses. It is estimated that 9 to 14 percent of healthy women suffer from menorrhagia. Because quantitative means of diagnosing menorrhagia are generally impractical, healthcare professionals often diagnose menorrhagia symptomatically by considering frequency of tampon or sanitary napkin change, spotting and staining events, presence of constant pain in the lower abdomen, interference with regular work and social routines and measurements of anemia.
Roberts LM, Woodford K, Zhou M, Black DS, Haggerty JE, Tate EH, Grindstaff KK, Mengesha W, Raman C, Zerangue N.; Expression of the thyroid hormone transporters MCT8 (SLC16A2) and OATP14 (SLCO1C1) at the blood-brain barrier, Endocrinology. 2008 Aug 7.
Roberts LM, Black DS, Raman C, Woodford K, Zhou M, Haggerty JE, Yan AT, Cwirla SE, Grindstaff KK.; Subcellular localization of transporters along the rat blood-brain barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation, Neuroscience. 2008 Aug 13;155(2):423-38.
Bhat L, Jandeleit B, Dias TM, Moors TL, Gallop MA.; Synthesis and biological evaluation of novel steroidal pyrazoles as substrates for bile acid transporters, Bioorg Med Chem Lett. 2005 Jan 3;15(1):85-7.
Cundy KC, Annamalai T, Bu L, De Vera J, Estrela J, Luo W, Shirsat P, Torneros A, Yao F, Zou J, Barrett RW, Gallop MA.; XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J Pharmacol Exp Ther. 2004 Oct;311(1):324-33.
Cundy KC, Branch R, Chernov-Rogan T, Dias T, Estrada T, Hold K, Koller K, Liu X, Mann A, Panuwat M, Raillard SP, Upadhyay S, Wu QQ, Xiang JN, Yan H, Zerangue N, Zhou CX, Barrett RW, Gallop MA.; XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther. 2004 Oct;311(1):315-23.