RESUMEN
The study objectives were to characterize the metabolism of nevirapine (NVP) in mouse, rat, rabbit, dog, monkey, and chimpanzee after oral administration of carbon-14-labeled or -unlabeled NVP. Liquid scintillation counting quantitated radioactivity and bile, plasma, urine, and feces were profiled by HPLC/UV diode array and radioactivity detection. Metabolite structures were confirmed by UV spectral and chromatographic retention time comparisons with synthetic metabolite standards, by beta-glucuronidase incubations, and in one case, by direct probe electron impact ionization/mass spectroscopy, chemical ionization/mass spectroscopy, and NMR. NVP was completely absorbed in both sexes of all species except male and female dogs. Parent compound accounted for <6% of total urinary radioactivity and <5.1% of total fecal radioactivity, except in dogs where 41 to 46% of the radioactivity was excreted as parent compound. The drug was extensively metabolized in both sexes of all animal species studied. Oxidation to hydroxylated metabolites occurred before glucuronide conjugation and excretion in urine and feces. Hydroxylated metabolites were 2-, 3-, 8-, and 12-hydroxynevirapine (2-, 3-, 8-, and 12-OHNVP). 4-carboxynevirapine, formed by secondary oxidation of 12-OHNVP, was a major urinary metabolite in all species except the female rat. Glucuronides of the hydroxylated metabolites were major or minor metabolites, depending on the species. Rat plasma profiles differed from urinary profiles with NVP and 12-OHNVP accounting for the majority of the total radioactivity. Dog plasma profiles, however, were similar to the urinary profiles with 12-OHNVP, its glucuronide conjugate, 4-carboxynevirapine, and 3-OHNVP glucuronide being the major metabolites. Overall, the same metabolites are formed in animals as are formed in humans.
Asunto(s)
Transcriptasa Inversa del VIH/antagonistas & inhibidores , Nevirapina/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Animales , Bilis/metabolismo , Biotransformación , Perros , Heces/química , Femenino , Glucuronidasa/metabolismo , Haplorrinos , Hidrólisis , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Tasa de Depuración Metabólica , Ratones , Nevirapina/sangre , Nevirapina/farmacología , Nevirapina/orina , Pan troglodytes , Conejos , Ratas , Factores Sexuales , Especificidad de la EspecieRESUMEN
The pharmacokinetics and biotransformation of the antiretroviral agent nevirapine (NVP) after autoinduction were characterized in eight healthy male volunteers. Subjects received 200-mg NVP tablets once daily for 2 weeks, followed by 200 mg twice daily for 2 weeks. Then they received a single oral dose (solution) of 50 mg containing 100 microCi of [(14)C]NVP. Biological fluids were analyzed for total radioactivity, parent compound (HPLC/UV), and metabolites (electrospray liquid chromatography/mass spectroscopy and liquid chromatography/tandem mass spectroscopy). Mean recovery of radioactivity was 91.4%, with 81.3% excreted in urine and 10.1% recovered in the feces over a period of 10 days. Circulating radioactivity was evenly distributed between whole blood and plasma. At maximum plasma concentration, parent compound accounted for approximately 75% of the circulating radioactivity. Mean plasma elimination half-lives for total radioactivity and NVP were 21.3 and 20.0 h, respectively. Several metabolites were identified in urine including 2-hydroxynevirapine glucuronide (18.6%), 3-hydroxynevirapine glucuronide (25.7%), 12-hydroxynevirapine glucuronide (23.7%), 8-hydroxynevirapine glucuronide (1.3%), 3-hydroxynevirapine (1.2%), 12-hydroxynevirapine (0.6%), and 4-carboxynevirapine (2.4%). Greater than 80% of the radioactivity in urine was made up of glucuronidated conjugates of hydroxylated metabolites of NVP. Thus, cytochrome P-450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of NVP biotransformation and elimination in humans. Only a small fraction of the dose (2.7%) was excreted in urine as parent compound.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Nevirapina/farmacocinética , Adulto , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/orina , Biotransformación , Cromatografía Líquida de Alta Presión , Heces/química , Semivida , Humanos , Hidrólisis , Masculino , Espectrometría de Masas , Nevirapina/sangre , Nevirapina/orina , Espectrofotometría Ultravioleta , Distribución TisularRESUMEN
Like other nonnucleoside inhibitors of HIV-1 reverse transcriptase, the dipyridodiazepinone nevirapine (Viramune, 1) selects for drug resistant variants of HIV-1, both in cell culture and in patients. In particular, the mutation of residue 181 from tyrosine to cysteine (Y181C) is associated with resistance to most reported nonnucleoside inhibitors. Introduction of an arylethyl substituent at the 8-position of the tricyclic dipyridodiazepinone skeleton confers enhanced potency against Y181C RT. Several analogues of this series display good broad spectrum potency against a panel of mutant enzymes.
Asunto(s)
Antivirales/síntesis química , Azepinas/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Mutación , Piridinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Sustitución de Aminoácidos , Antivirales/química , Antivirales/farmacología , Azepinas/química , Azepinas/farmacología , Línea Celular Transformada , Farmacorresistencia Microbiana , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/genética , Humanos , Técnicas In Vitro , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Nevirapina/química , Nevirapina/farmacología , Piridinas/química , Piridinas/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
Nevirapine (I) is the first human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor to reach regulatory approval. As a result of a second generation program around the tricyclic core system of nevirapine, 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-(2-(pyridin-4-yl)ethyl)-6H-dipyrido[3, 2-b:2',3'-e][1,4]diazepin-6-one (II)1a and 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-phenylethyl-6H-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-one (III)1a were identified as broad spectrum HIV-1 RT inhibitors. A detailed examination of replacing either of the methylenes of the 8-ethyl linker of II or III is presented. It was found that 8-aryloxymethyl and 8-arylthiomethyl are the preferred pattern of substitution for potency against RT. The most potent compounds were further evaluated against a panel of clinically significant mutant RT enzymes (K103N, V106A, G190A, P236L) and in cytotoxicity and in vitro metabolism assays. The most potent compound was 2-chloro-8-phenylthiomethyl analogue 37 which displayed sub-100 nM activity against all HIV-1 RT enzymes tested.
Asunto(s)
Antivirales/síntesis química , Azepinas/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Nevirapina/análogos & derivados , Piridinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Animales , Antivirales/química , Antivirales/farmacología , Azepinas/química , Azepinas/farmacología , Disponibilidad Biológica , Línea Celular Transformada , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Farmacorresistencia Microbiana , Estabilidad de Medicamentos , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/fisiología , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Mutación , Nevirapina/síntesis química , Nevirapina/química , Nevirapina/farmacocinética , Nevirapina/farmacología , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
In these Phase I/II open-label clinical trials, 62 persons with human immunodeficiency virus type 1 (HIV-1) infection and CD4+ cell counts < 400/mm3 received nevirapine at doses of 12.5, 50, and 200 mg/day, alone or in combination with zidovudine, 200 mg q8h. Nevirapine was well tolerated in the doses tested. Mean steady-state trough levels were 0.23, 1.1, and 1.9 micrograms/ml for the 12.5, 50, and 200 mg/day doses, respectively. Early suppression of p24 antigen levels and increase in CD4+ cell count were reversed following rapid emergence of virus less susceptible to nevirapine. Resistant strains were isolated from all participants by 8 weeks. Nevertheless, reduction of p24 antigen levels to < 50% of baseline values persisted for 12 weeks or more in four of seven persons who received 200 mg nevirapine/day in combination with zidovudine: these individuals had been antigenemic on long-term zidovudine therapy. This study demonstrates a direct relationship between drug resistance and effects on surrogate markers in HIV-1 infection.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Piridinas/uso terapéutico , Zidovudina/uso terapéutico , Adulto , Recuento de Linfocito CD4 , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Proteína p24 del Núcleo del VIH/sangre , Infecciones por VIH/sangre , Humanos , Masculino , Persona de Mediana Edad , Nevirapina , Piridinas/efectos adversos , Piridinas/farmacocinética , Inhibidores de la Transcriptasa Inversa , Estados UnidosRESUMEN
BI-L-226, a 2,6-disubstituted 4-(2-arylethenyl)phenol, is a potent and selective 5-lipoxygenase inhibitor which shows excellent inhibition of antigen-induced leukotriene generation in the lung of cynomolgus monkeys by aerosol administration, although little activity has been observed by the p.o. route. The facile synthesis of the succinate ester BI-L-357, however, results in a prodrug which has p.o. activity between 10 to 30 mg/kg in an ex vivo whole blood model of leukotriene B4 generation in both squirrel and cynomolgus monkeys. In addition, the prodrug is effective in inhibiting pulmonary leukotriene C4 production in antigen-challenged cynomolgus monkeys in the same dose range. Plasma levels of the parent compound in the monkey after p.o. administration of 30 mg/kg are 25-fold higher than the IC50 needed for in vitro inhibition of leukotriene B4 in whole blood. Absolute bioavailability of the parent compound was 50%. The prodrug concept therefore extends the potential of this class of compounds to inflammation sites mediated by 5-lipoxygenase not readily treated by topical administration.
Asunto(s)
Inhibidores de la Lipooxigenasa/farmacología , Fenoles/farmacología , Profármacos/farmacología , Tiofenos/farmacología , Animales , Antígenos , Disponibilidad Biológica , Calcimicina/farmacología , Femenino , Humanos , Leucotrieno B4/biosíntesis , Leucotrieno B4/sangre , Inhibidores de la Lipooxigenasa/farmacocinética , Pulmón/metabolismo , Macaca fascicularis , Masculino , Fenoles/sangre , Fenoles/farmacocinética , Profármacos/farmacocinética , SRS-A/antagonistas & inhibidores , SRS-A/biosíntesis , Saimiri , Tiofenos/sangre , Tiofenos/farmacocinética , Tromboxano B2/biosíntesis , Tromboxano B2/sangreRESUMEN
Nevirapine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, was administered for the first time to humans in a pilot study designed to investigate the pharmacokinetics and tolerance of the drug following single-dose administration to 21 HIV-1-infected individuals. The study followed a parallel design. Different groups of three subjects each were given one of seven dose levels (2.5 to 400 mg) in sequential order, starting with the lowest dose. Each subject received only one dose. Nevirapine was rapidly absorbed at all doses from a tablet formulation. Peak concentrations in plasma were generally achieved within 90 min of dose administration. Secondary peaks were also noted between 3 and 12 h or between 24 and 28 h, the latter being noted mainly in subjects receiving the higher doses. After 24 h, concentrations in plasma declined in a log-linear fashion. The terminal half-life and mean residence time exceeded 24 h in all but one subject, indicating a prolonged disposition time in this population. Both peak concentrations in plasma and areas under the plasma concentration-time curves increased proportionally with increasing dose from 2.5 to 200 mg; however, the increase in the peak concentration in plasma and the area under the plasma concentration-time curve appeared to be less than proportional at the 400-mg dose level in this small number of subjects. This observation may be due to increased clearance or decreased absorption at the highest dose or population differences in absorption or clearance between doses. Studies with a cross-over design are planned to resolve these issues. The pharmacokinetic characteristics of nevirapine are appropriate for once-daily administration. A daily 12.5-mg dose is predicted to achieve trough concentrations in plasma in the range required to totally inhibit replication of wild-type HIV-1 in human T-cell culture.
Asunto(s)
Antivirales/farmacocinética , Piridinas/farmacocinética , Síndrome de Inmunodeficiencia Adquirida/metabolismo , Adulto , Antivirales/efectos adversos , Antivirales/sangre , Femenino , Infecciones por VIH/metabolismo , VIH-1/enzimología , Semivida , Humanos , Absorción Intestinal , Masculino , Persona de Mediana Edad , Nevirapina , Piridinas/efectos adversos , Piridinas/sangreAsunto(s)
Ácido Homovanílico/sangre , Esquizofrenia/sangre , Antipsicóticos/uso terapéutico , Estudios de Seguimiento , Hospitalización , Humanos , Evaluación de Procesos y Resultados en Atención de Salud , Pronóstico , Esquizofrenia/diagnóstico , Esquizofrenia/tratamiento farmacológico , Psicología del EsquizofrénicoRESUMEN
A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a Ki of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (greater than 8000) in culture.
Asunto(s)
Antivirales/farmacología , VIH-1/efectos de los fármacos , Piridinas/farmacología , Inhibidores de la Transcriptasa Inversa , Replicación Viral/efectos de los fármacos , Animales , Línea Celular , VIH-1/enzimología , VIH-1/fisiología , Humanos , Cinética , Estructura Molecular , Nevirapina , Inhibidores de la Síntesis del Ácido Nucleico , Piridinas/síntesis químicaRESUMEN
Previous studies of the effects of chronic low-dose amphetamine (2 mg/kg per day X 21 days) on the spontaneous discharge rate of cerebellar Purkinje neurons have shown persistent depressant effects for up to 50 days after cessation of drug administration. The depression of spontaneous discharge observed was only partially reversible by various pharmacological agents which disrupt noradrenergic neurotransmission in cerebellum. In the present study, several additional approaches were used to investigate further this persistent effect. Rats were treated, either before or after chronic treatment with amphetamine, with intracisternal 6-hydroxydopamine at doses which destroy most noradrenergic fibers in cerebellum. In either case Purkinje neurons were still significantly slowed after cessation of amphetamine treatment, although the depression was not as great as previously observed. In another experiment, cerebellar cortical levels of 3-methoxy, 4-hydroxy phenyl glycol (MHPG) were measured after cessation of amphetamine administration, to determine if there was biochemical evidence for increased noradrenergic neurotransmission. At ten days, MHPG levels were elevated by 36%, and they returned to control values by 30 days. The evidence obtained in these studies suggests that chronic amphetamine treatment causes a persistent increase in noradrenergic neurotransmission, but non-noradrenergic mechanisms may also be important mechanisms in the long-lasting depression of activity of cerebellar Purkinje neurons.
Asunto(s)
Anfetamina/farmacología , Cerebelo/efectos de los fármacos , Norepinefrina/farmacología , Animales , Estimulación Eléctrica , Hidroxidopaminas/farmacología , Metoxihidroxifenilglicol/análisis , Oxidopamina , Propranolol/farmacología , Células de Purkinje/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
Plasma levels of homovanillic acid (HVA), a dopamine metabolite, were examined in 19 psychiatric inpatients during maintenance treatment on neuroleptic medications. A significant positive correlation was found between the level of HVA and the severity of tardive dyskinesia (TD) in these patients. Seven patients had their medication discontinued for 12 days. In spite of a fall in neuroleptic levels to negligible values, plasma HVA levels remained essentially stable while scores on the Abnormal Involuntary Movement Scale (AIMS) fell only slightly. The data support the hypothesis that some forms of TD may involve a persistent increase in presynaptic dopaminergic activity.
Asunto(s)
Antipsicóticos/efectos adversos , Discinesia Inducida por Medicamentos/sangre , Ácido Homovanílico/sangre , Fenilacetatos/sangre , Adulto , Antipsicóticos/sangre , Discinesia Inducida por Medicamentos/etiología , Femenino , Humanos , Masculino , Trastornos Mentales/tratamiento farmacológico , Persona de Mediana EdadAsunto(s)
Clonidina/farmacología , Glándulas Endocrinas/metabolismo , Glicoles/sangre , Metoxihidroxifenilglicol/sangre , Síndrome de Tourette/sangre , Adolescente , Adulto , Niño , Hormona del Crecimiento/sangre , Humanos , Hidrocortisona/sangre , Masculino , Prolactina/sangre , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
Measures of plasma 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) may be useful for investigating noradrenergic function in certain behavioral and physiologic states. Serial plasma and urine samples were obtained from a diagnostically heterogeneous group of ten psychiatric inpatients over a three- to five-day period. The plasma samples were assayed for free and total MHPG and the urine samples for total MPHG. The variance between patients in both plasma free and conjugated MHPG was markedly greater than the variance within patients. The test-retest reliability for free plasma MHPG in both AM vs PM values within and across study days was also significant for both free and conjugated MHPG even though the AM plasma free MHPG values were significantly greater than the PM values. No significant correlations were found between plasma free and conjugated MHPG or between urinary total MHPG and plasma free MHPG.
Asunto(s)
Glicoles/sangre , Metoxihidroxifenilglicol/sangre , Trastornos del Humor/sangre , Esquizofrenia/sangre , Adulto , Femenino , Humanos , Masculino , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/orina , Persona de Mediana Edad , Norepinefrina/metabolismo , Proyectos PilotoRESUMEN
A direct method has been employed to estimate the rate of production by human brain of 3-methoxy-4-hydroxyphenethyleneglycol, the major metabolite of brain norepinephrine, a brain neurotransmitter. Venous specimens were obtained from the internal jugular vein from ten awake human subjects at a puncture site above the common facial vein, the first major source of extracranial inflow. Arterial specimens were simultaneously obtained from the radial artery. Plasma samples were assayed and a highly significant difference was found in the concentration of the metabolite in plasma coming out of the brain (venous blood) as compared to plasma entering the brain (arterial blood). This venous-arterial difference was calculated to be 0.7 +/- 0.1 nanogram per milliliter of blood. Assuming an adult brain weight of 1400 grams and normal cerebral blood flow, it is estimated that the rate of production of 3-methoxy-4-hydroxyphenethyleneglycol by the awake human brain is approximately 597 nanograms per minute or 35.8 micrograms per hour. Urine specimens were also collected from six of these subjects during a period of 1 to 3.5 hours, which bracketed the time the blood samples were obtained. For these six subjects the output of 3-methyoxy-4-hydroxyphenethyleneglycol by whole brain was estimated to be 40.9 micrograms per hour, whereas the rate of its excretion into urine was 64.5 micrograms per hour.
Asunto(s)
Encéfalo/metabolismo , Glicoles/metabolismo , Metoxihidroxifenilglicol/metabolismo , Adulto , Circulación Cerebrovascular , Femenino , Humanos , Masculino , Metoxihidroxifenilglicol/sangre , Metoxihidroxifenilglicol/orina , Persona de Mediana Edad , Norepinefrina/metabolismoRESUMEN
The concentrations of dopamine (DA) metabolites (free and conjugated) was measured in plasma and brain regions of rats by the mass spectrometric method of selected ion monitoring. Experimental treatments which altered the function of central dopamine neurons also induced concomitant changes in plasma 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Stimulation of the nigrostriatal pathway increased plasma DOPAC and HVA whereas lesion of the pathway decreased plasma metabolites. Several drug treatments induced parallel changes in brain and plasma concentrations of DA metabolites. It is suggested that changes in the concentration of DOPAC and HVA in rat brain are reflected by parallel changes in plasma. No conjugated forms of DOPAC and HVA were found in plasma and brain tissue of vervet monkeys (Cercopithecus aethiops).