RESUMO
A limited number of studies with application of the Arrhenius equation have been reported to drugs and biopharmaceuticals in biological fluids at frozen temperatures. This paper describes stability studies of ampicillin and cephalexin in aqueous solution and human plasma applying the Arrhenius law for determination of adequate temperature and time of storage of these drugs using appropriate statistical analysis. Stability studies of the beta-lactams in human plasma were conducted at temperatures of 20°C, 2°C, -20°C and also during four cycles of freeze-thawing. Chromatographic separation was achieved using a Shimpak C(18) column, acetonitrile as organic modifier and detection at 215nm. LC-UV-MS/MS was used to demonstrate the conversion of ampicillin into two diastereomeric forms of ampicilloic acid. Stability studies demonstrated degradation greater than 10% for ampicillin in human plasma at 20°C, 2°C and -20°C after 15h, 2.7days, 11days and for cephalexin at the same temperatures after 14h, 3.4days and 19days, respectively, and after the fourth cycle of freezing-thawing. The Arrhenius plot showed good prediction for the ideal temperature and time of storage for ampicillin (52days) and cephalexin (151days) at a temperature of -40°C, but statistical analysis (least squares method) must be applied to avoid incorrect extrapolations and estimated values out uncertainty limits.
Assuntos
Ampicilina/sangue , Antibacterianos/sangue , Cefalexina/sangue , Modelos Químicos , Ampicilina/química , Antibacterianos/química , Cefalexina/química , Cromatografia Líquida de Alta Pressão , Temperatura Baixa , Interpretação Estatística de Dados , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Análise dos Mínimos Quadrados , Modelos Lineares , Estrutura Molecular , Espectrometria de Massas em Tandem , Fatores de TempoRESUMO
The aims of this study were to describe and compare the pharmacokinetics of a single dose of cephalexin (10 mg/kg) after its intravenous (i.v.) administration to five goats in three different physiological status: nonpregnant nonlactating (NPNL), pregnant (P) and nonpregnant lactating (L). Blood samples were collected at predetermined times, and plasma concentrations of cephalexin were measured by microbiological assay. Relevant pharmacokinetic parameters were calculated using noncompartmental analysis. Statistical comparison was performed applying the nonparametric anova. No significant differences were found for cephalexin pharmacokinetic parameters between the L and the NPNL group. Median V(dss) was significantly lower in pregnant goats (0.09 [0.07-0.10] L/kg) compared with NPNL goats (0.16 [0.14-0.49] L/kg). Median total Cl and V(dz) were significantly lower in pregnant goats (0.25 [0.19-0.29] L/h·kg and 0.11 [0.10-0.13] L/kg, respectively) than in lactating goats (0.40 [0.32-0.57] L/h·kg and 0.20 [0.14-0.23] L/kg, respectively). Median AUC(0-∞) was significantly higher in pregnant goats (37.79 [34.75-52.10] µg·h/mL) than in lactating goats (25.11 [17.44-31.14] µg·h/mL). Our study showed that even though some pharmacokinetic parameters of cephalexin are altered in pregnant and lactating goats, these differences are unlikely to be of clinical importance; therefore, no dose adjustment would be necessary during pregnancy and lactation.
Assuntos
Antibacterianos/farmacocinética , Cefalexina/farmacocinética , Cabras/metabolismo , Lactação/metabolismo , Prenhez/metabolismo , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Cefalexina/administração & dosagem , Cefalexina/sangue , Feminino , Injeções Intravenosas/veterinária , GravidezRESUMO
This study describes and compares the pharmacokinetics of a single 7.5mg/kg dose of cephalexin monohydrate oil-based 20% suspension after its administrations to six cows by the intramuscular (i.m.) and subcutaneous (s.c.) routes, and to five calves by the i.m. route. Significantly (P<0.05) higher peak plasma concentrations (5.6+/-0.79microg/ml versus 3.93+/-1.24microg/ml) and lower half-life (1.81+/-0.56h versus 4.21+/-0.82h) and mean residence time (4.12+/-1.07h versus 6.63+/-0.85h) were obtained after i.m. administration when compared to the s.c. administration to cows. No differences were found between pharmacokinetic parameters calculated for cows and calves. Cephalexin plasma concentrations remained above 0.5-0.75microg/ml for 11-14h and 8-9h after the s.c. and i.m. administrations, respectively. Thus, route of administration may be an important issue to be considered when calculating dosage schedules for successful treatments and safe withdrawal times for veterinary medicines.
Assuntos
Cefalexina/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/farmacocinética , Área Sob a Curva , Bovinos , Cefalexina/administração & dosagem , Cefalexina/sangue , Feminino , Meia-Vida , Injeções , CarneRESUMO
The purpose of this study was to investigate whether previous administration of metoclopramide affects cephalexin pharmacokinetics after its oral administration in dogs as well as whether these changes impair its predicted clinical efficacy. Six healthy beagle dogs were included in this study. Oral 25 mg/kg cephalexin monohydrate and intravenous 0.5 mg/kg metoclopramide HCl single doses were administered. Each dog received cephalexin or cephalexin following metoclopramide, with a 2-week washout period. Plasma concentrations of cephalexin were determined by microbiological assay. Cephalexin peak plasma concentration and area under the curve from 0 to infinity significantly increased from 18.77+/-2.8 microg/mL and 82.65+/-10.4 microg.h/mL to 21.88+/-0.8 microg/mL and 113.10+/-20.9 microg.h/mL, respectively, after pretreatment with metoclopramide. No differences between treatments were found for other pharmacokinetic parameters. Pharmacokinetic/pharmacodynamic indices calculated for highly susceptible staphylococci were similar for both experiences. Metoclopramide pretreatment may have increased cephalexin absorption by affecting its delivery to the intestine, and/or enhancing intestinal transporter PEPT1 function. Neither difference in the efficacy of cephalexin nor an increase in toxicity is expected as a result of this modification. Consequently, no dose adjustment is required in cephalexin-treated patients pretreated with metoclopramide.
Assuntos
Antibacterianos/farmacocinética , Antieméticos/farmacologia , Cefalexina/farmacocinética , Cães/metabolismo , Metoclopramida/farmacologia , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antieméticos/administração & dosagem , Antieméticos/sangue , Área Sob a Curva , Cefalexina/administração & dosagem , Cefalexina/sangue , Infusões Intravenosas/veterinária , Absorção Intestinal , Metoclopramida/administração & dosagem , Metoclopramida/sangueRESUMO
Recent studies have identified a 24 h rhythm in the expression and function of PEPT1 in rats, with significantly higher levels during the nighttime than daytime. Similarly, temporal variations have been described in glomerular filtration rate and renal blood flow, both being maximal during the activity phase and minimal during the rest phase in laboratory rodents. The aim of this study was to assess the hypothesis that the absorption of the first-generation cephalosporin antibiotic cephalexin by dogs would be less and the elimination would be slower after evening (rest span) compared to morning (activity span) administration, and whether such administration-time changes could impair the medication's predicted clinical efficacy. Six (3 male, 3 female; age 4.83+/-3.12 years) healthy beagle dogs were studied. Each dog received a single dose of 25 mg/kg of cephalexin monohydrate per os at 10:00 and 22:00 h, with a two-week interval of time between the two clock-time experiments. Plasma cephalexin concentrations were determined by microbiological assay. Cephalexin peak plasma concentration was significantly reduced to almost 77% of its value after the evening compared to morning (14.52+/-2.7 vs. 18.77+/-2.8 microg/mL) administration. The elimination half-life was prolonged 1.5-fold after the 22:00 h compared to the 10:00 h administration (2.69+/-0.9 vs. 1.79+/-0.2 h). The area under the curve and time to reach peak plasma concentration did not show significant administration-time differences. The duration of time that cephalexin concentrations remained above the minimal inhibitory concentrations (MIC) for staphylococci susceptiblity (MIC=0.5 microg/mL) was>70% of each of the 12 h dosing intervals (i.e., 10:00 and 22:00 h). It can be concluded that cephalexin pharmacokinetics vary with time of day administration. The findings of this acute single-dose study require confirmation by future steady-state, multiple-dose studies. If such studies are confirmatory, no administration-time dose adjustment is required to ensure drug efficacy in dogs receiving an oral suspension of cephalexin in a dosage of 25 mg/kg at 12 h intervals.
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Cefalexina/administração & dosagem , Cefalexina/farmacocinética , Administração Oral , Animais , Antibacterianos/sangue , Antibacterianos/farmacocinética , Cefalexina/sangue , Cefalexina/farmacologia , Fenômenos Cronobiológicos , Cães , Feminino , MasculinoRESUMO
The aims of this study were to describe and compare the pharmacokinetic profiles and T(>MIC90) of two commercially available once-daily recommended cephalexin formulations in healthy adult dogs administered by the intramuscular (i.m.) route. Six beagle dogs received a 10 mg/kg dose of an 18% parenteral suspension of cephalexin of laboratory A (formulation A) and laboratory B (formulation B) 3 weeks apart. Blood samples were collected in predetermined times after drug administration. The main pharmacokinetic parameters were (mean +/- SD): AUC((0-infinity)), 72.44 +/- 15.9 and 60.83 +/- 13.2 microg.h/mL; C(max), 10.11 +/- 1.5 and 8.50 +/- 1.9 microg/mL; terminal half-life, 3.56 +/- 1.5 and 2.57 +/- 0.72 h and MRT((0-infinity)), 5.86 +/- 1.5 and 5.36 +/- 1.2 h for formulations A and B, respectively. T(>MIC90) was 63.1 +/- 14.7 and 62.1 +/- 14.7% of the dosing interval for formulations A and B, respectively. Median (range) for t(max) was 2.0 (2.0-3.0) h and 3.0 (2.0-4.0) for formulations A and B, respectively. Geometric mean ratios of natural log-transformed AUC((0-infinity)) and C(max) and their 90% confidence intervals (CI) were 0.84 (0.72-0.98) and 0.83 (0.64-1.07), respectively. The plasma profiles of cephalexin following the administration of both formulations were similar. No statistical differences between pharmacokinetic parameters or T(>MIC90) were observed, however, bioequivalence between both formulations could not be demonstrated, as lower 90% CI failed to fell within the selected range of 80-125% for bioequivalence.
Assuntos
Antibacterianos/farmacocinética , Cefalexina/farmacocinética , Cães/metabolismo , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Cefalexina/administração & dosagem , Cefalexina/sangue , Química Farmacêutica , Esquema de Medicação , Feminino , Injeções Intramusculares/veterinária , MasculinoRESUMO
Serum bactericidal titers against Staphylococcus aureus were measured in 63 children who were receiving mafcillin or methicillin intravenously, or dicloxacillin, penicillin, or cephalexin orally. The SBTs obtained following unit does of 25 mg/kg of dicloxacillin, 35 mg/kg of penicillin, or 25 mg/kg of cephalexin with probenecid were comparable to those seen following intravenous doses of 40 mg/kg nafcillin or methicillin. Twenty-two children with acute hematogenous osteomyelitis proven or presumed to be due to S. aureus were treated intravenously until point tenderness and fever had resolved, and then with oral therapy. The mean duration of intravenous therapy was 14 days. Oral doses were adjusted so that a peak SBT of greater than or equal to 1:16 and a trough SBT of greater than or equal to 1:2 were obtained in most children. No recurrences occurred. The SBT proved to be a practical means of assessing the adequacy of oral therapy in children with infections due to S. aureus.