Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Efavirenz (EFV, Sustiva, Stocrin, DMP-266, L-743,726) is a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Pharmacokinetics of EFV was studied in rats and monkeys, the safety assessment species. In rats, after 2 and 5 mg/kg i.v. administrations, the mean CLp, Vdss, and T1/2 were 67 ml/min/kg, 5.0 liters/kg, and 1 h, respectively. EFV was metabolized completely, and the products were excreted almost exclusively via bile. At the higher dose of 15 mg/kg, the CLp was reduced by 36%, implying saturation of metabolism processes. A similar phenomenon occurred in monkeys, where the CLp declined by 60% as the i.v. dose was increased from 5 to 15 mg/kg. After oral dosing, the bioavailability of EFV in rats (10 mg/kg) and monkeys (2 mg/kg) was 16% and 42%, respectively. Higher doses in both species led to disproportionate increases in the AUC and higher Tmax values, suggesting saturation of metabolism and/or prolongation of absorption. The delay in Tmax was more pronounced in monkeys where the plasma concentrations reached plateaus and were sustained for 4 to 20 h. In rats, the prolongation of absorption was due to delayed gastric emptying as demonstrated by >10-fold slower transit of [14C]polyethylene glycol through the stomach of EFV-pretreated animals. The delayed gastric emptying in monkeys also was observed when the animals dosed at 160 mg/kg exhibited emesis, 8 h postdose, which was found to contain a substantial portion of the dose. These results demonstrated that in rats and monkeys, both delayed gastric emptying and saturation of metabolic processes played significant roles in the nonlinear pharmacokinetics of EFV.
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PMID:Nonlinear pharmacokinetics of efavirenz (DMP-266), a potent HIV-1 reverse transcriptase inhibitor, in rats and monkeys. 988 7

Efavirenz (Sustiva) is a potent and specific inhibitor of the HIV-1 reverse transcriptase and is approved for the treatment of HIV infection. The metabolism of efavirenz in different species has been described previously. Efavirenz is primarily metabolized in rats to the glucuronide conjugate of 8-OH efavirenz. Electrospray ionization-liquid chromatography/mass spectrometry analyses of bile samples from rats dosed with either efavirenz or with 8-OH efavirenz revealed three polar metabolites, M9, M12, and M13, with pseudomolecular ions [M-H](-) at m/z 733, 602, and 749, respectively. The characteristic mass spectral fragmentation patterns obtained for metabolites M9 and M13 suggested that these were glutathione-sulfate diconjugates, and the presence of a glutathione moiety in metabolite M9 was confirmed by liquid chromatograpy/nuclear magnetic resonance (NMR) analysis of bile extracts. Metabolite M12 was characterized by liquid chromatography/mass spectrometry as a glucuronide-sulfate diconjugate. Unambiguous structures of M9, M12, and M13 were obtained from one-dimensional proton and carbon NMR as well as proton-proton (correlated spectroscopy, two-dimensional shift correlation), proton-carbon heteronuclear multiple quantum correlation, and long-range proton-carbon (heteronuclear multiple bond correlation) correlated two-dimensional NMR analyses of metabolites isolated from rat bile. The mass spectral and NMR analyses of M10, which was isolated from rat urine, suggested a cysteinylglycine-sulfate diconjugate. The isolation of these polar metabolites for further characterization by NMR was aided by mass spectral analyses of HPLC fractions and solid phase extraction extracts during the isolation steps. The complete characterization of these novel diconjugates demonstrates that further phase II metabolism of polar conjugates such as sulfates could take place in vivo.
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PMID:Liquid chromatography/mass spectrometry and high-field nuclear magnetic resonance characterization of novel mixed diconjugates of the non-nucleoside human immunodeficiency virus-1 reverse transcriptase inhibitor, efavirenz. 1046 Aug 5

Efavirenz (Sustiva, Fig. 1) is a potent and specific inhibitor of HIV-1 reverse transcriptase approved for the treatment of HIV infection. To examine the potential differences in the metabolism among species, liquid chromatography/mass spectrometry profiles of efavirenz metabolites in urine of rats, guinea pigs, hamsters, cynomolgus monkeys, and humans were obtained and compared. The metabolites of efavirenz were isolated, and structures were determined unequivocally by mass spectral and NMR analyses. Efavirenz was metabolized extensively by all the species as evidenced by the excretion of none or trace quantities of parent compound in urine. Significant species differences in the metabolism of efavirenz were observed. The major metabolite excreted in the urine of all species was the O-glucuronide conjugate (M1) of the 8-hydroxylated metabolite. Efavirenz was also metabolized by direct conjugation with glucuronic acid, forming the N-glucuronide (M2) in all five species. The sulfate conjugate of 8-OH efavirenz (M3) was found in the urine of rats and cynomolgus monkeys but not in humans. In addition to the aromatic ring-hydroxylated products, metabolites with a hydroxylated cyclopropane ring (at C14) were also isolated. GSH-related products of efavirenz were identified in rats and guinea pigs. The cysteinylglycine adduct (M10), formed from the GSH adduct (M9), was found in significant quantities in only rat and guinea pig urine and was not detected in other species. In vitro metabolism studies were conducted to show that the GSH adduct was produced from the cyclopropanol intermediate (M11) in the presence of only rat liver and kidney subcellular fractions and was not formed by similar preparations from humans or cynomolgus monkeys. These studies indicated the existence of a specific glutathione-S-transferase in rats capable of metabolizing the cyclopropanol metabolite (M11) to the GSH adduct, M9. The biotransformation pathways of efavirenz in different species were proposed based on some of the in vitro results.
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PMID:Identification and characterization of efavirenz metabolites by liquid chromatography/mass spectrometry and high field NMR: species differences in the metabolism of efavirenz. 1053 18

Efavirenz (SUSTIVA, DMP 266, EFV) is a novel non-nucleoside reverse transcriptase inhibitor, which shows good inhibitory activity against HIV-1. The pharmacokinetics of efavirenz allow for once daily dosing without regard to meals of normal composition. Efavirenz is a mild inducer of CYP 3A4. Clinically significant drug interactions have been reported with medications that are metabolised via the cytochrome P450 enzymes such as indinavir and saquinavir. Results from the studies collated for submission (003, 006, 020, 024 and ACTG 364) have demonstrated the potency and durability of once daily efavirenz in combination with zidovudine (AZT) + lamivudine (3TC), indinavir (IDV), nelfinavir (NFV), IDV + 2 NRTIs, and NFV + 2 NRTIs. Efavirenz was recently approved for commercial use in the USA and has received marketing authorisation in Europe and Canada.
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PMID:Clinical history of efavirenz. 1062 35

Several studies have been performed to investigate the appropriate dose of efavirenz (SUSTIVA, DMP 266, EFV) for the treatment of HIV infection. When considering the most appropriate dose, virological, pharmacological, clinical and safety data from these studies were examined. Efavirenz 600 mg once daily is the recommended dose of efavirenz for combination therapy in adults. Efavirenz 600 mg once daily adjusted for body size is the appropriate dose for combination therapy in children three years of age or older.
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PMID:Dose-ranging studies. 1062 36

Gilead Sciences will offer an expanded access program for its anti-HIV agent, adefovir (Preveon). Prospective enrollees must have CD4 counts less than 50, a viral load of over 30,000 copies/ml by PCR within the past 2 months, and failed at least two nucleoside analogs and one protease inhibitor. Because adefovir has extremely modest activity, it can only function as an adjunct to other potent drug combinations. There is concern that the eligibility requirements will be problematic. DuPont Merck's non-nucleoside reverse transcriptase inhibitor Sustiva is undergoing participant registration for its expanded access program. Participants must have CD4 counts less than 50 but may have any viral load level. Glaxo's expanded access program for abacavir (1592U89) is an open-label trial with eligibility being CD4 counts less than 100. Glaxo has also opened an expanded access program for patients with moderate to severe AIDS dementia.
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PMID:Three drugs now in expanded access. 1136 20

DuPont Merck is opening an expanded access program for efavirenz (Sustiva), a non-nucleoside reverse transcriptase inhibitor (NNRTI). Efavirenz (formerly called DMP-266), the most potent NNRTI to date, is taken only once a day. To participate, patients must be failing therapy or be intolerant of current therapy. The patients are required to take the drug with another anti-HIV drug that they have never taken. Contact information for efavirenz studies, including a pediatric trial, is provided.
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PMID:DMP 266 (Sustiva) expanded access. 1136 50

Although there have been great strides in AIDS research, there is no major development on the horizon that is capturing the attention of the press. However, there are significant developments being made in a number of areas. Current antiretroviral treatments are leading to declines in AIDS deaths and infections in the United States and studies are leading to a greater understanding of treatment failures and the role of compliance and adherence. Three new antiretrovirals are available in expanded access programs: abacavir (1592), efavirenz (Sustiva, DMP-266), and adefovir dipivoxil (Preveon, bis-POM PMEA). New treatment approaches will deal with restoring immune function, using vaccines to prevent HIV and opportunistic infection, and developing more antiretrovirals to combat the disease. The role of managed care and providing treatment to the uninsured and underinsured are also issues to be addressed in the coming year.
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PMID:1998 outlook: treatment; research; access. 1136 51

As many as 25 to 45 percent of patients using triple therapy with protease inhibitors will develop resistance due to a change in the genetic HIV code. However, patients who develop resistance may still benefit clinically when protease inhibitors are used in combination with other antiretrovirals. These patients may not have undetectable viral loads although they may have stable T4-cell counts. Resistance does not always lead to disease progression. Newer drugs under development or available through compassionate track programs may benefit people with resistance. DMP-266 (Sustiva) is a non-nucleoside reverse transcriptase inhibitor that shows promise for these patients. Other drugs in development include Compound 141, 1592, and adefovir.
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PMID:Understanding and managing resistance. 1136 97

Some of the latest developments in HIV treatment are described and contact information is given for people seeking further information on the topic. Clinical studies and preliminary results for interleukin-2 (IL-2), 1592U89 (abacavir), DMP-266 (efavirenz or Sustiva), and 141W94 (VX-94, Vertex) are described. Pharmaceutical companies are expected to continue developing new HIV drugs, including those in new drug classes, that will be more convenient, palatable, and less prone to resistance.
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PMID:What's new and what's next. 1136 53


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