RESUMO
The kinetics of tolrestat, a potent inhibitor of aldose reductase, were examined. Serum concentrations of tolrestat and of total 14C were measured after dosing normal subjects and subjects with diabetes with 14C-labeled tolrestat. In normal subjects, tolrestat was rapidly absorbed and disappearance from serum was biphasic. Distribution and elimination t 1/2s were approximately 2 and 10 to 12 hr, respectively, after single and multiple doses. Unchanged tolrestat accounted for the major portion of 14C in serum. Radioactivity was rapidly and completely excreted in urine and feces in an approximate ratio of 2:1. Findings were much the same in subjects with diabetes. In normal subjects, the kinetics of oral tolrestat were independent of dose in the 10 to 800 mg range. Repetitive dosing did not result in unexpected cumulation. Tolrestat was more than 99% bound to serum protein; it did not compete with warfarin for binding sites but was displaced to some extent by high concentrations of tolbutamide or salicylate.
Assuntos
Naftalenos/metabolismo , Absorção , Adulto , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Tipo 1/metabolismo , Relação Dose-Resposta a Droga , Humanos , Cinética , Masculino , Naftalenos/sangue , Ligação ProteicaRESUMO
The pharmacokinetics and metabolic fate of the antihyperlipidemic drug acifran were assessed after a single oral dose of the 14C-labeled drug to healthy male volunteers. Peak serum acifran and radioactivity concentrations were attained 1 to 2 hours after dosing, and the drug was eliminated with a half-life of 1.6 hours. Virtually all of the recovered dose was excreted in the urine. All of the serum and urinary radioactivity was caused by unconjugated acifran. In patients with moderate chronic renal failure, the binding of acifran to plasma proteins was decreased, and the plasma concentrations of total and unbound drug were greater than those of healthy subjects. Renal failure substantially reduced the plasma and renal clearance of total and particularly of unbound acifran, moderately reduced its volume of distribution, and increased its elimination half-life from 1.4 to 1.7 hours to 5.7 hours. The results show that acifran is very well absorbed, is rapidly eliminated, is excreted in the urine, and does not undergo any detectable biotransformation in healthy human subjects.
Assuntos
Furanos/farmacocinética , Hipolipemiantes/farmacocinética , Falência Renal Crônica/metabolismo , Adulto , Análise de Variância , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia em Camada Fina , Fezes/análise , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/urina , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Taxa de Depuração MetabólicaRESUMO
OBJECTIVE: To evaluate the effects of coadministration of loratadine and erythromycin on the pharmacokinetics and electrocardiographic repolarization (QTc) pharmacodynamics of loratadine and its metabolite descarboethoxyloratadine in healthy volunteers. METHODS: Twenty-four healthy volunteers were studied in a prospective, double-blind crossover design while confined in a Clinical Research Center. The primary pharmacodynamic end point of the study was the difference between baseline and day 10 mean QTc intervals obtained from surface electrocardiograms. Plasma concentrations of loratadine, descarboethoxyloratadine, and erythromycin were measured on treatment day 10 for pharmacokinetic analysis. Subjects received in random sequence the following three treatments for 10 consecutive days during three separate study periods: 10 mg loratadine every morning plus 500 mg erythromycin stearate every 8 hours, or 10 mg loratadine every morning plus placebo every 8 hours, or placebo every morning plus 500 mg erythromycin stearate. RESULTS: Concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine (40% increase in area under the plasma concentration-time curve [AUC]) and descarboethoxyloratadine (46% increase in AUC) compared with loratadine alone. Analysis of variance showed no difference between the treatment groups in effect on QTc intervals compared with baseline, and no significant change from baseline was observed. No clinically relevant changes in the safety profile of loratadine were observed, and there were no reports of sedation nor syncope. CONCLUSION: Although concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine and descarboethoxyloratadine, no clinically relevant changes in the safety profile of loratadine were observed. In this study, 10 mg loratadine administered orally for 10 consecutive days was well tolerated when coadministered with therapeutic doses of erythromycin stearate.
Assuntos
Antibacterianos/farmacologia , Eletrocardiografia/efeitos dos fármacos , Eritromicina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Loratadina/farmacologia , Adulto , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Estudos Cross-Over , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Quimioterapia Combinada , Eritromicina/efeitos adversos , Eritromicina/farmacocinética , Estudos de Avaliação como Assunto , Genótipo , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Humanos , Loratadina/efeitos adversos , Loratadina/farmacocinética , Masculino , Oxigenases de Função Mista/antagonistas & inibidores , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Estudos ProspectivosRESUMO
Groups of male rats were fed various doses of clofibrate and diosgenin, both alone and in combination for 1 week. Clofibrate suppressed the diosgenin-induced increase in hepatic cholesterol synthesis but did not alter the effectiveness of diosgenin in reducing cholesterol absorption. Diosgenin did not affect the bioavailability of CPIB. Clofibrate reduced the diosgenin induced increase in biliary levels of cholesterol; none of the regimens altered biliary bile acids. The combination produced greater decreases in LDL cholesterol than did either compound alone; the diosgenin-induced elevation in HDL cholesterol was partially reversed by clofibrate. The data provide a basis for the combined use of clofibrate and diosgenin in the control of hyperlipoproteinemia.
Assuntos
Anticolesterolemiantes/uso terapêutico , Colesterol/metabolismo , Clofibrato/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Fígado/metabolismo , Espirostanos/uso terapêutico , Absorção , Animais , Anticolesterolemiantes/administração & dosagem , Disponibilidade Biológica , Colesterol/biossíntese , Clofibrato/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Ratos , Espirostanos/administração & dosagemRESUMO
Rats, dogs and squirrel monkeys were given a single oral dose of [4-(14)C]diosgenin. Virtually all of the radioactivity was excreted in the feces. All of the absorbed radioactivity was eliminated via the bile. The percent of dose absorbed decreased with increasing dose. The amount of radioactivity in livers of rats given [4-(14)C]diosgenin was less than that after [4-(14)C]cholesterol, but more than after [4-(14)C]beta-sitosterol. Absorbed radioactivity in rats distributed into tissues, most notably the liver, adrenals, and walls of the gastrointestinal tract. No serum diosgenin was detected after a single large dose to rats and dogs. After multiple doses (100 mg/kg/day for 4 weeks) of diosgenin to dogs, up to 15 micrograms/ml of unchanged diosgenin was found in serum. Serum from human subjects receiving 3 g/day of diosgenin for 4 weeks contained less than 1 microgram/ml of unchanged drug. After a single dose of [14C]diosgenin, several metabolites were detected in the bile of rats and dogs; the pattern of metabolites was dissimilar in the two species. No diosgenin or 7-hydroxydiosgenin was found. One of the major biliary metabolites was diosgenin monohydroxylated in the F ring, but the location of the hydroxyl group was different in the two species. Although rat caecal contents were capable of reducing diosgenin to smilagenin in vitro, no smilagenin was present in the feces of rats given chow supplemented with diosgenin. It was concluded that diosgenin is poorly absorbed in the species tested, and that the amount which is absorbed undergoes extensive biotransformation.
Assuntos
Diosgenina/metabolismo , Sapogeninas/metabolismo , Animais , Autorradiografia , Biotransformação , Colesterol/metabolismo , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Absorção Intestinal , Masculino , Taxa de Depuração Metabólica , Ratos , Saimiri , Distribuição TecidualRESUMO
The effect of AY-25,712 (2-methyl-2-phenyl-3(2H)-furanone-5-carboxylic acid) on serum lipids, hepatic lipogenesis and biliary cholesterol was investigated in male rats. Based on one-week treatment, the minimal effective dose of AY-25,712 which lowered serum triglycerides was 1 mg/kg/day, and LDL-cholesterol, 5 mg/kg/day. Nicotinic acid produced a similar lipid-lowering profile albeit at 5 times higher doses. AY-25,712 at doses of 2 mg/kg/day and higher significantly increased the ratio of HDL to total cholesterol. Unlike clofibrate, AY-25,712 did not increase liver weight or liver mitochondrial alpha-glycerophosphate dehydrogenase, nor increase biliary cholesterol levels in rats fed a diet containing 2% cholesterol and 0.5% cholic acid. AY-25,712 lowered serum cholesterol, triglycerides and phospholipids in rats rendered hyperlipidemic with Triton WR-1339 and decreased the elevated serum triglycerides in streptozotocin-diabetic rats. [14C]Acetate incorporation into cholesterol by liver homogenate was suppressed in rats given AY-25,712 p.o. for 1 week. The results show that AY-25,712 is a potent LDL-cholesterol- and triglyceride-lowering agent in rats, and that its lipid-lowering profile differs from that of clofibrate but resembles that of nicotinic acid.
Assuntos
Furanos/farmacologia , Hipolipemiantes/farmacologia , Animais , Ácidos e Sais Biliares/análise , Colesterol/análise , Colesterol/biossíntese , Diabetes Mellitus Experimental/complicações , Glicerolfosfato Desidrogenase/metabolismo , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/complicações , Lipídeos/análise , Lipídeos/sangue , Fígado/análise , Fígado/enzimologia , Masculino , Polietilenoglicóis/administração & dosagem , Ratos , Ratos EndogâmicosRESUMO
The effect of AY-25,712 [2-methyl-2-phenyl-3(2H)-furanone-5-carboxylic acid] on various aspects of free fatty acid (FFA) and triglyceride metabolism was studied in male rats. Serum triglycerides were lowered by a single oral dose of AY-25,712 or nicotinic acid, but not of clofibrate. Unlike with clofibrate, when AY-25,712 or nicotinic acid was given in the diet, serum triglycerides were not affected. In vitro, both AY-25,712 and nicotinic acid suppressed the theophylline-induced FFA release by epididymal fat pads, but had no effect on lipolysis induced by norepinephrine. Both AY-25,712 and nicotinic acid enhanced the activity of adipose tissue lipoprotein lipase. The initial decrease in plasma FFA and triglycerides, and in liver triglycerides after a single oral dose of nicotinic acid was followed by a rebound to levels which, at later time intervals, wee significantly higher than in controls. AY-25,712 was more potent than nicotinic acid in lowering plasma FFA and triglycerides as well as liver triglycerides, but produced no such rebound effect. The data show that, except for the absence of this rebound effect, the mode of action of AY-25,712 in rats resembles that of nicotinic acid and differs from that of clofibrate.
Assuntos
Ácidos Graxos/sangue , Furanos/farmacologia , Hipolipemiantes/farmacologia , Tecido Adiposo/metabolismo , Animais , Ácidos Graxos não Esterificados/sangue , Hipolipemiantes/administração & dosagem , Lipase Lipoproteica/metabolismo , Masculino , Niacina/administração & dosagem , Niacina/farmacologia , Ratos , Ratos Endogâmicos , Triglicerídeos/sangueRESUMO
The non-sedating anti-histamine, loratadine [ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin- 11-ylidene-1-piperidinecarboxylate], was administered orally in the diet to mature male rats at dosages of 4, 10 and 25 mg/kg/day for 2 weeks. The effects of these treatments on liver microsomal cytochrome P450 were evaluated by immunochemical and biochemical techniques, and were compared with the effects of treating rats with three different inducers of cytochrome P450, namely phenobarbital, 3-methylcholanthrene and dexamethasone. Treatment of rats with loratadine caused a dose-dependent increase in the levels of P450 2B1 and 2B2, the major phenobarbital-inducible P450 enzymes, as determined by Western immunoblotting. At the highest dosage tested, loratadine was less effective than phenobarbital as an inducer of 2B1 and 2B2, although the induction of these proteins could be detected immunochemically even at the lowest dosage of loratadine tested. Consistent with these observations, treatment of rats with loratadine caused a dose-dependent increase in the rate of two reactions that are catalyzed predominantly by 2B1/2, namely testosterone 16 beta-hydroxylation and 7-pentoxyresorufin O-dealkylation. At the highest dosage tested, loratadine caused a 7.3- and 8.5-fold increase in the rate of testosterone 16 beta-hydroxylation and 7-pentoxyresorufin O-dealkylation, respectively, compared with a 22- and 45-fold increase caused by phenobarbital treatment. Treatment of rats with loratadine caused a 1.4- to 2.0-fold increase in the 2 beta-, 6 beta- and 15 beta-hydroxylation of testosterone, which was associated with a similar increase in the levels of immunoreactive P450 3A1 and/or 3A2. As an inducer of P450 3A1/2, loratadine was slightly less effective than phenobarbital, and was considerably less effective than dexamethasone, which caused a 10- to 33-fold increase in testosterone 2 beta-, 6 beta- and 15 beta-hydroxylase activity. At the dosages tested, loratadine did not increase the levels of P450 1A1, the major 3-methylcholanthrene-inducible P450 enzyme, as determined by Western immunoblotting. The rate of 7-ethoxyresorufin O-dealkylation, which is catalyzed predominantly by P450 1A1, increased 1.9-fold after loratidine treatment, but this increase was less than that caused by phenobarbital treatment (2.2-fold), and was considerably less than that caused by 3-methylcholanthrene treatment (33-fold). The effects of treating mature male mice with loratadine on liver microsomal cytochrome P450 resembled the effects observed in rats. These results indicate that loratadine is a phenobarbital-type inducer of liver microsomal cytochrome P450 in rats and mice.
Assuntos
Ciproeptadina/análogos & derivados , Sistema Enzimático do Citocromo P-450/biossíntese , Antagonistas dos Receptores Histamínicos/farmacologia , Isoenzimas/biossíntese , Microssomos Hepáticos/efeitos dos fármacos , Animais , Ciproeptadina/administração & dosagem , Ciproeptadina/farmacologia , Citocromo P-450 CYP1A1 , Citocromo P-450 CYP2B1 , Sistema Enzimático do Citocromo P-450/metabolismo , Indução Enzimática/efeitos dos fármacos , Immunoblotting , Loratadina , Masculino , Camundongos , Microssomos Hepáticos/enzimologia , Oxirredutases/metabolismo , Fenobarbital/farmacologia , Ratos , Ratos Endogâmicos , Relação Estrutura-Atividade , Testosterona/metabolismoRESUMO
[3H]Loratadine was incubated with human liver microsomes to determine which cytochrome P450 (CYP) enzymes are responsible for its oxidative metabolism. Specific enzymes were identified by correlation analysis, by inhibition studies (chemical and immunoinhibition), and by incubation with various cDNA-expressed human P450 enzymes. Descarboethoxyloratadine (DCL) was the major metabolite of loratadine detected following incubation with pooled human liver microsomes. Although DCL can theoretically form by hydrolysis, the conversion of loratadine to DCL by human liver microsomes was not inhibited by the esterase inhibitor phenylmethylsulfonyl fluoride (PMSF), and was dependent on NADPH. A high correlation (r2 = 0.96, N = 10) was noted between the rate of formation of DCL and testosterone 6 beta-hydroxylation, a CYP3A-mediated reaction. With the addition of ketoconazole (CYP3A4 inhibitor) to the incubation mixtures, the residual rate of formation of DCL correlated (r2 = 0.81) with that for dextromethorphan O-demethylation, a CYP2D6 reaction. Rabbit polyclonal antibodies raised against the rat CYP3A1 enzyme (5 mg IgG/nmol P450) and troleandomycin (0.5 microM), a specific inhibitor of CYP3A4, decreased the formation of DCL by 53 and 75%, respectively, when added to 1.42 microM loratadine microsomal incubations. Quinidine (5 microm), a CYP2D6 inhibitor, inhibited the formation of DCL approximately 20% when added to microsomal incubations of loratadine at concentrations of 7-35 microM. Incubation of loratadine with cDNA-expressed CYP3A4 and CYP2D6 microsomes catalysed the formation of DCL with formation rates of 135 and 633 pmol/min/nmol P450, respectively. The results indicated that loratadine was metabolized to DCL primarily by the CYP3A4 and CYP2D6 enzymes in human liver microsomes. In the presence of a CYP3A4 inhibitor, loratadine was metabolized to DCL by the CYP2D6 enzyme. Conformational and electrostatic analysis of loratadine indicated that its structure is consistent with substrate models for the CYP2D6 enzyme.
Assuntos
Sistema Enzimático do Citocromo P-450/análise , Antagonistas dos Receptores Histamínicos H1/metabolismo , Loratadina/metabolismo , Microssomos Hepáticos/enzimologia , Oxigenases de Função Mista/análise , Piperidinas/análise , Piridinas/análise , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antimaláricos/farmacologia , Sítios de Ligação , Biotransformação , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Humanos , Técnicas In Vitro , Cetoconazol/farmacologia , Microssomos Hepáticos/metabolismo , Oxigenases de Função Mista/antagonistas & inibidores , Modelos Moleculares , Oxirredução , Quinidina/farmacologia , Proteínas Recombinantes/antagonistas & inibidores , Especificidade por Substrato , Troleandomicina/farmacologiaRESUMO
PIP: The effects of 2,8-dibenzylcyclooctanone (DBCO) and a series of its analogues on serum lipids and on estrogenic activity in rats were studied. Assays of the estrogenicity of DBCO showed that although the compound is a very weak estrogen, it exhibited estrogenic activity at doses that were hypolipidemic. Among the analogues, only those containing the dibenzylcyclooctanone system were active. All compounds demonstrating hypocholesterolemic activity, except the weakly active compound 15, also reduced the weights of the seminal vesicles and ventral prostate and increased the weight of the adrenal gland. Compounds containing a benzylidene group or reduced ketone group did not exhibit any activity. It is concluded that the hypocholesterolemic activity of the structural analogues of DBCO is correlated with their estrogenicity.^ieng
Assuntos
Cicloparafinas/farmacologia , Estrogênios/biossíntese , Hipolipemiantes , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Anticolesterolemiantes , Compostos de Benzil/farmacologia , Lipídeos/sangue , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Glândulas Seminais/efeitos dos fármacos , Estimulação QuímicaRESUMO
STUDY OBJECTIVE: To determine the penetration of ceftibuten into various respiratory tissues and fluids. DESIGN: Single-dose, open-label, pharmacokinetic study. SETTING: Veterans Administration Medical Center. PATIENTS: Twelve hospitalized men aged 34 to 75 years with a variety of noninfectious pulmonary symptoms/diseases. INTERVENTIONS: Patients received a single oral dose of ceftibuten, 200 mg, prior to undergoing diagnostic fiberoptic bronchoscopy. Plasma samples for the determination of ceftibuten concentrations were collected pretreatment and up to 12 h postdosing. Nasal secretions, tracheal secretions, BAL fluid, and lung tissue from a biopsy were obtained at bronchoscopy from 2 to 7 h postdosing. MEASUREMENTS AND RESULTS: Mean pharmacokinetic parameters for ceftibuten in plasma were the following: maximum observed plasma concentration (Cmax), 8.77 microg/mL; time to reach Cmax, 2.2 h; area under the plasma concentration-time curve extraploated to infinity, 49.21 microg/h/mL; and terminal elimination half-life, 3.17 h. These parameters were similar to those obtained in studies using healthy volunteers. Mean penetration of ceftibuten into nasal, tracheal, and bronchial secretions was 47%, 50%, and 30%, respectively. Mean penetration into BAL fluid was 81%, whereas penetration into lung tissue was 39%. No patient experienced any adverse effects related to ceftibuten. CONCLUSIONS: Ceftibuten penetrates well into various tissues and fluids of the upper and lower respiratory tracts. The results support the activity of ceftibuten in the treatment of upper and lower respiratory tract infections.
Assuntos
Cefalosporinas/farmacocinética , Sistema Respiratório/metabolismo , Doenças Respiratórias/metabolismo , Adulto , Idoso , Líquido da Lavagem Broncoalveolar , Broncoscopia , Ceftibuteno , Cefalosporinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição TecidualRESUMO
These studies were conducted to assess the systemic bioavailability of mometasone furoate (MF) administered by both the dry-powder inhaler (DPI) and the metered-dose inhaler with an alternate propellant (MDI-AP). The pharmacokinetics of single doses (400 micrograms) of MF administered by intravenous (i.v.) and inhalation routes was assessed in a randomized, three-way crossover study involving 24 healthy volunteers. In a separate study, 6 healthy subjects were administered a single dose of tritiated (3H-) MF by DPI, and the radioactivity in blood, urine, feces, and expired air was determined. Following i.v. administration, MF was detected in all subjects for at least 8 hours postdose. The half-life (t1/2) following i.v. administration was 4.5 hours. In contrast, following DPI administration, plasma MF concentrations were below the limit of quantification (LOQ, 50 pg/mL) for many subjects (10 of 24), and the systemic bioavailability by this route was estimated to be less than 1%. Only two plasma samples following MDI-AP administration had plasma concentrations of MF above the LOQ indicating no detectable systemic bioavailability in 92% of the subjects. A separate study with 6 healthy male subjects administered a single dose of 3H-MF (200 microCi) by DPI revealed that much of the dose (approximately 41%) was excreted unchanged in the feces (0-72 hours), while that which was absorbed was extensively metabolized. These results indicate that inhaled MF has negligible systemic bioavailability and is extensively metabolized and should therefore be well tolerated in the chronic treatment of asthma.
Assuntos
Anti-Inflamatórios/farmacocinética , Pregnadienodiois/farmacocinética , Absorção , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Humanos , Masculino , Furoato de Mometasona , Nebulizadores e Vaporizadores , Pós , Pregnadienodiois/administração & dosagemRESUMO
The effect of a high-fat breakfast on the bioavailability of the components of an extended-release tablet containing 10 mg loratadine in the immediate-release coating and 240 mg pseudoephedrine sulfate in the extended-release core was studied in 24 healthy male volunteers in a single-dose, two-way crossover study. The drug was administered after a 10-hour overnight fast or within 5 minutes of consuming a standardized high-fat breakfast. Serial blood samples were collected over a 48-hour period, and plasma was analyzed for loratadine and its active metabolite descarboethoxyloratadine (DCL), and pseudoephedrine. For pseudoephedrine, maximum concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUCzero-infinity) were similar after both treatments, indicating no relevant food effect on the bioavailability of pseudoephedrine. Also, the absorption profiles of pseudoephedrine (from Wagner-Nelson analysis) were similar for the fed and fasted treatments, indicating no apparent differences in absorption. Plasma concentration-time profiles and values for Cmax and AUCzero-infinity of DCL were similar for the two treatments, indicating no relevant food effect on the pharmacokinetics of DCL. In contrast, for loratadine, administration with food resulted in a significantly increased mean Cmax (53%) and AUC from time zero to the final quantifiable sample (AUCif) (76%). However, the resultant Cmax and AUC of loratadine under fed conditions were well below those previously obtained at steady-state after multiple-dose administration of loratadine (40 mg/day) that were shown to be safe and well-tolerated in several clinical studies. The effect of food on the bioavailability and pharmacokinetic profiles of the components of a combination loratadine/pseudoephedrine extended-release tablet is not likely to be clinically significant.
Assuntos
Efedrina/farmacocinética , Interações Alimento-Droga , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Loratadina/farmacocinética , Vasoconstritores/farmacocinética , Adulto , Análise de Variância , Disponibilidade Biológica , Cromatografia , Estudos Cross-Over , Preparações de Ação Retardada , Combinação de Medicamentos , Efedrina/administração & dosagem , Efedrina/efeitos adversos , Efedrina/sangue , Meia-Vida , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Antagonistas dos Receptores Histamínicos H1/sangue , Humanos , Loratadina/administração & dosagem , Loratadina/efeitos adversos , Loratadina/sangue , Masculino , Vasoconstritores/administração & dosagem , Vasoconstritores/efeitos adversos , Vasoconstritores/sangueRESUMO
Isepamicin is a new aminoglycoside antibiotic with activity against both gram-negative and gram-positive bacteria. The pharmacokinetics of isepamicin were evaluated after a 0.5-hour intravenous infusion of alpha 15-mg/kg dose to groups of young adults and geriatric volunteers. Isepamicin was safe and well tolerated. No adverse events related to the infusion were reported. As age increased, there were increases in the elimination phase half-life (t1/2 beta) and the area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity), and decreases in systemic (Cl) and renal clearance (Clr). The changes seen in Cl with age were a result of changes in renal function estimated by creatinine clearance (Clcr). There were no apparent correlations between age and maximum plasma concentration (Cmax), half-life of the tau-phase (t1/2 tau), volume of distribution at steady-state (Vdss), or the amount of isepamicin excreted in urine within 24 hours after dose administration (Ae24 hrs). When comparing the elderly (61-80 years old) with the younger (21-60 years) volunteers, the (AUC0-infinity), and t1/2 beta values were higher in the elderly and the Cl and Clr values were lower, but Cmax, t1/2 tau and Vdss were similar in the two age groups. The contribution of the tau-phase to the overall AUC was minimal and similar for the two age groups. Also, there were no gender effects on the pharmacokinetics of isepamicin in both the young and elderly volunteers. These results demonstrate that changes in the pharmacokinetics of isepamicin in the elderly are attributable to changes in renal function, whereas age, per se, is not a significant factor.
Assuntos
Antibacterianos/farmacocinética , Adulto , Fatores Etários , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Feminino , Gentamicinas/administração & dosagem , Gentamicinas/sangue , Gentamicinas/farmacocinética , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
The comparative bioavailability of ceftibuten, a new third-generation cephalosporin antibiotic given orally once daily, in capsule and suspension dosage forms, was assessed in healthy male subjects. In three separate studies, subjects received either a 400-mg dose as a suspension or one laboratory-batch, 400-mg capsule; one laboratory-batch, 400-mg capsule or two laboratory-batch, 200-mg capsules; or one production-batch, 400-mg capsule or two laboratory-batch, 200-mg capsules. Plasma samples were assayed for ceftibuten using high-performance liquid chromatography, and the data were assessed using pharmacokinetic and statistical methods. Confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve extrapolated to infinity were within 80% to 125% of guidelines, demonstrating the bioequivalence of the two treatments within each of the three studies. One 400-mg capsule (laboratory or production batch) was bioequivalent to two 200-mg capsules used in a clinical efficacy trial; the 400-mg suspension was bioequivalent to a 400-mg capsule (laboratory batch). Thus we concluded that the capsule and the suspension dosage forms were bioequivalent.
Assuntos
Cefalosporinas/administração & dosagem , Cefalosporinas/farmacocinética , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Cápsulas , Ceftibuteno , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Relação Dose-Resposta a Droga , Infecções por Bactérias Gram-Negativas/sangue , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/sangue , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Masculino , Valores de Referência , Suspensões , Equivalência TerapêuticaRESUMO
Eptifibatide, a synthetic peptide inhibitor of the platelet glycoprotein IIb/IIIa receptor, has been studied as an antithrombotic agent in a variety of acute ischemic coronary syndromes. The purpose of the present study was to characterize the disposition of 14C-eptifibatide in man after a single intravenous (i.v.) bolus dose. 14C-Eptifibatide (approximately 50 microCi) was administered to eight healthy men as a single 135-microgram/kg i.v. bolus. Blood, breath carbon dioxide, urine, and fecal samples were collected for up to 72 hours postdose and analyzed for radioactivity by liquid scintillation spectrometry. Plasma and urine samples were also assayed by liquid chromatography with mass spectrometry for eptifibatide and deamidated eptifibatide (DE). Mean (+/- SD) peak plasma eptifibatide concentrations of 879 +/- 251 ng/mL were achieved at the first sampling time (5 minutes), and concentrations then generally declined biexponentially, with a mean distribution half-life of 5 +/- 2.5 minutes and a mean terminal elimination half-life of 1.13 +/- 0.17 hours. Plasma eptifibatide concentrations and radioactivity declined in parallel, with most of the radioactivity (82.4%) attributed to eptifibatide. A total of approximately 73% of administered radioactivity was recovered in the 72-hour period following 14C-eptifibatide dosing. The primary route of elimination was urinary (98% of the total recovered radioactivity), whereas fecal (1.5%) and breath (0.8%) excretion was small. Eptifibatide is cleared by both renal and nonrenal mechanisms, with renal clearance accounting for approximately 40% of total body clearance. Within the first 24 hours, the drug is primarily excreted in the urine as unmodified eptifibatide (34%), DE (19%), and more polar metabolites (13%).
Assuntos
Peptídeos/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Adulto , Área Sob a Curva , Biotransformação , Coleta de Amostras Sanguíneas , Radioisótopos de Carbono , Desaminação , Eptifibatida , Humanos , Injeções Intravenosas , Masculino , Peptídeos/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagemRESUMO
Male albino rats were administered various oral doses of tibric acid daily for 1 week. Serum cholesterol and triglyceride levels were reduced, but total liver content of cholesterol, phospholipids, and triglycerides was increased. Tibric acid treatment suppressed the incorporation of both [14C] acetate and [3H] mevalonate into cholesterol by liver homogenates.
Assuntos
Colesterol/biossíntese , Hipolipemiantes/farmacologia , Fígado/metabolismo , Piperidinas/farmacologia , Acetatos/metabolismo , Animais , Fígado/efeitos dos fármacos , Masculino , Ácido Mevalônico/metabolismo , Fosfolipídeos/metabolismo , Ratos , Triglicerídeos/metabolismoRESUMO
In a crossover design four male dogs were given orally or i.v. [14C]isosorbide dinitrate (ISDN) or [14C]isosorbide-2-mononitrate (2-ISMN) at a dose of 1 mg kg-1 (70-80 microCi). Virtually all of the oral dose was absorbed and all of the radioactivity was excreted in the urine. The profile of serum radioactivity was similar after all drug administrations. ISDN was rapidly denitrated, giving rise to isosorbide-5-mononitrate (5-ISMN) as a major metabolite, and 2-ISMN as a minor metabolite. The apparent elimination half-life from serum of 2-ISMN and 5-ISMN was 2-3 h. More than 50% of the serum radioactivity after [14C]2-ISMN was due to unchanged drug. The apparent volume of distribution of 2-ISMN averaged 8.3 litres. The results show that, in contrast to ISDN, administration of 2-ISMN resulted in relatively high unchanged drug levels in the serum; the disposition of radioactivity after [14C]ISMN was however similar to that after [14C]ISDN. The findings support the concept that the concentrations of ISDN, 2-ISMN and 5-ISMN in the blood are inversely related to the rates of denitration, and that the vascular activity of the nitrates of isosorbide relates to the rates of their dinitration.
Assuntos
Dinitrato de Isossorbida/análogos & derivados , Dinitrato de Isossorbida/metabolismo , Absorção , Animais , Radioisótopos de Carbono , Cães , Meia-Vida , MasculinoRESUMO
The metabolic disposition of pelrinone, a cardiotonic drug, was studied in mouse, rat, rabbit, dog, monkey and man. Pelrinone was rapidly and extensively absorbed in rodents, dogs, monkeys and man. Except in rabbits, the major portion of the serum radioactivity was due to parent drug. Pelrinone was moderately bound to human serum proteins and weakly bound to serum proteins from animals. Radioactive compounds were rapidly eliminated from rat tissues with the highest concentrations found in organs associated with absorption and elimination. After a 1.0 mg/kg i.v. dose, the rapid elimination of pelrinone from mouse, rat and dog serum precluded estimation of an elimination half life (t1/2). However, after higher oral or i.v. doses, a more prolonged elimination phase was apparent and the t1/2 of pelrinone ranged from 8-10 h in rodents and dogs. In human subjects given escalating oral or i.v. doses of pelrinone, the elimination t1/2 was independent of dose and averaged 1-2 h. The serum AUC of pelrinone was linearly dose-related following oral doses up to 20 mg/kg in dogs and 100 mg in man. In mice, a greater proportional increase in AUC occurred between oral doses of 2-100 mg/kg while in rats, the serum AUC increased in less than proportional manner from 10-200 mg/kg p.o. In all species, radioactive compounds were excreted mainly in the urine. No metabolites were detected in dog and human urine while small amounts of unconjugated metabolites were excreted in mouse and rat urine.