Disposition of phenytoin in critically ill trauma patients

Estimates of phenytoin pharmacokinetic variables and protein binding were determined in 10 adult critically ill trauma patients. Each study subject received phenytoin sodium as an intravenous loading dose of 15 mg/kg, followed by an initial intravenous maintenance dose of 6 mg/kg/day. Serial blood samples were obtained throughout the seven-day study period and analyzed for total and unbound serum phenytoin concentrations. The concentration data for each patients were fitted to a one-compartment model with elimination defined by the Michaelis-Menten constant Km and the maximum rate of metabolism (Vmax) and to a one-compartment model with first-order elimination. The Michaelis-Menten model used Bayesian parameter estimation while the linear model used weighted non-linear least-squares regression analysis. Unbound phenytoin fraction ranged from 0.073 to 0.25. Free fraction increased 7% to 108% in 9 of 10 patients (median increase 29%) from day 1 to day 7 of therapy. Variable estimates using the Michaelis-Menten model were as follows: volume of distribution, 0.76 +/- 0.15 L/kg (0.58-1.01 L/kg); Vmax, 568 +/- 197 mg/day (350-937 mg/day); and Km, 4.5 +/- 1.8 mg/L (1.8-6.2 mg/L). These estimates fell within the wide range of values obtained in studies using stable patients or healthy volunteers. The Michaelis-Menten model was significantly less biased and more precise than the linear model. Three of four patients who continued to receive their study maintenance dose had substantially lower measured total serum concentrations of phenytoin than predicted using the study variable estimates.(ABSTRACT TRUNCATED AT 250 WORDS)     

The biological availability of cefadroxil given simultaneously with N-acetylcysteine]

A preliminary study revealed that similarly to the antibiotics amoxillin, thiamphenicol, erythromycin and doxycycline, the oral cephalosporin cefadroxil (CAS 66592-87-8) can be administered simultaneously with the mucolytic n-acetylcysteine (CAS 616-91-1). In the present study 12 healthy male volunteers received in a randomised cross-over design a single oral dose of 1000 mg cefadroxil or a single oral dose of 1000 mg cefadroxil (Bidocef) plus 200 mg n-acetylcysteine. The two study days were separated by a wash-out period of one week. To determine the pharmacokinetic profile of cefadroxil, plasma and sputum were analysed by HPLC at defined intervals. Regarding the bioavailability of cefadroxil, the free combination is bioequivalent to the individual component. After administration of cefadroxil plus n-acetylcysteine, a higher cefadroxil concentration was found in the sputum compared to an administration of cefadroxil alone. However, the difference was not statistically significant. According to the results, simultaneous administration of the oral cephalosporin cefadroxil and the mucolytic n-acetylcysteine is possible without changes in the bioavailability of cefadroxil being observed.     

Theophylline. Pooled Michaelis-Menten parameters (Vmax and Km) and implications

The literature on theophylline is confusing since in the same dose range one article will report linear kinetics while another will report non-linear kinetics. Single dose clearances and lower steady-state clearances of theophylline, recently reported in the literature, were used to estimate pooled Vmax and Km values of the Michaelis-Menten equation for 10 normal subjects. The mean Vmax was 1960 mg/day and the mean Km was 24.1 mg/L. These values were then utilised to: explain another set of different oral clearances following doses of 2 and 6 mg/kg reported in the literature; estimate relative effects of dose rate and type of input on absolute bioavailability; estimate AUC (0-infinity) as a function of single dose over the range 0 to 1500 mg; estimate the average steady-state serum concentration of theophylline (Cssav and steady-state oral clearance (CLsspo) as a function of dose rate in mg/day; illustrate how Michaelis-Menten kinetics alters the apparent first-order elimination rate constant and the half-life estimated from terminal log-linear plots at concentrations appreciably lower than the Km value; and illustrate how Michaelis-Menten kinetics affects the estimation of a zero-order absorption rate constant using the Wagner-Nelson method.     

Dose-dependent absorption and elimination of cefadroxil in man

Summary The pharmacokinetic behaviour of cefadroxil was dose-dependent in healthy male volunteers following the oral administration of single doses of 5, 15, and 30 mg · kg^–1.As the dose of cefadroxil increased from 5 to 15 and 30 mg · kg^–1, the peak plasma concentrations, normalized to 5 mg · kg^–1, decreased significantly from 15.1 to 10.7 and 7.6 mg·l^–1, while the corresponding normalized areas under the plasma concentration-time curves from 0 to 2 h decreased significantly from 1258 to 946 and 801 min·mg·l^–1.When the same subjects were given 5 mg·kg^–1 of cefadroxil together with 45 mg·kg^–1 of cephalexin, the absorption of cefadroxil was slowed to a similar or greater extent than with the high dose of cefadroxil.Although the absorption rate decreased as the dose increased, the systemic availability of cefadroxil was essentially complete at all doses, as judged by the 24 h urinary recoveries of the antibiotic. Kinetic analysis of the plasma concentration-time curves gave the best fit with a zero-order followed by a first-order absorption process, consistent with saturable intestinal absorption of cefadroxil.The elimination rate of cefadroxil was directly related to dose and plasma concentrations, and the clearance at the dose of 5 mg·kg^–1 was significantly increased by the simultaneous administration of high-dose cephalexin.The renal clearance of cefadroxil ranged from 98 ml·min·l^–1 at total plasma cephalosporin (cefadroxil + cephalexin) concentrations less than 2.5 mg·l^–1 to 156 mg·l^–1 at concentrations greater than 40 mg·l^–1. These findings are consistent with saturable active gastrointestinal absorption and renal tubular reabsorption of cefadroxil, with competitive inhibition of both processes by cephalexin.     

Pharmacokinetics of ABT-773, a new semi-synthetic ketolide in neutropenic lung-infected mice: a population approach

ABT-773 is an investigational ketolide antimicrobial agent with an in-vitro bactericidal activity against macrolide-susceptible and -resistant Streptococcus pneumoniae. The pharmacokinetics of this drug candidate were evaluated in lung-infected (108 CFU mL 1 starting inoculum) mice following a single dose (25, 50, 100 or 200 mg kg(-1)) oral administration as a solution in 10% of 95% ethanol and 90% of 0.1 M pH 6.5 phosphate buffer solution. Serum ABT-773 concentrations were measured using a validated HPLC assay with fluorescence detection (excitation at 324 nm and emission at 364 nm). Population pharmacokinetic analysis was performed using the NONMEM computer program. Results from data analysis showed non-linear pharmacokinetics of ABT-773, noted by the increases in half-life (3.1 to 27.2 h) and AUC/dose (23.7 to 149 mg h(-1) L(-1) mg(-1)), with doses from 25 to 200 mg kg(-1). A non-linear one-compartment model with parallel capacity-limited and linear first-order elimination best described the pharmacokinetics of ABT-773 in the mouse. The total volume of distribution was 0.316 L. The clearance for the linear first-order elimination was 0.0027 L h(-1). The Vm and Km were 0.0385 L h(-1) and 0.141 mg L(-1), respectively, for the capacity-limited elimination.     

Kinetics of the intestinal uptake of zinc acexamate in normal and zinc-depleted rats

The uptake of zinc as acexamic acid salt in the small intestine of the anaesthetized rat was shown to be a two-phase process in normal animals. The first phase is rapid mucosal binding which satisfies the Freundlich isotherm equation and which involves about 30 per cent of the initially perfused zinc. The second phase was characterized as an apparent absorption step which obeys Michaelis-Menten and first-order combined kinetics, with the following parameters: Vm = 6.51 mg h-1; Km = 2.96 mg; ka = 0.306 h-1. In largely non-saturated conditions, an apparent global rate constant of about 2.50 h-1 was calculated. No significant interference due to endogenous zinc excretion into the small intestine was observed during the absorption period. In zinc-deficient animals, the two phases were not so well characterized. Binding was non-linear and apparent absorption efficiency was much greater at high zinc concentrations, so no evidence of saturable kinetics was found, thus confirming the hypothesis of a homeostatic zinc regulation mechanism.     

Pharmacokinetic modelling of pentoxifylline and lisofylline after oral and intravenous administration in mice

The aim of this study was to develop pharmacokinetic models for pentoxifylline (PTX) and the R(-)-enantiomer of the PTX metabolite 1, lisofylline (LSF), in order to identify some factors influencing the absorption of these compounds from the intestines and to clarify mechanisms involved in their non-linear pharmacokinetics. Serum samples were collected after oral and intravenous administration of PTX and LSF to male CD-1 mice at two different doses. In addition, both compounds under investigation were coadministered with a modulator of drug transporters, verapamil, and an inhibitor of cytochrome P450 (CYP) 3A4, ketoconazole. Pharmacokinetic analysis revealed that a one-compartment model with Michaelis-Menten type absorption and elimination best described the pharmacokinetics of PTX, whereas the LSF concentration-time data were adequately fitted to a two-compartment model with a first-order absorption and Michaelis-Menten type elimination process. Both coadministered compounds significantly decreased the area under the concentration-time curve from 0 to 60 min calculated for PTX and increased the value of this parameter for LSF. The results of this study indirectly suggest that saturation of drug transport across intestinal cells and elimination from the central compartment may be responsible for the non-linear pharmacokinetics of PTX, whereas in the case of LSF, the dose dependency in the pharmacokinetics is solely related to the elimination from the central compartment. It seems that the observed changes in PTX and LSF concentrations after coadministration with verapamil and ketoconazole may be clinically significant, especially after chronic treatment, however further studies are necessary to assess the importance of these interactions in humans.     

Comparative bioavailability of two cefadroxil products using serum and urine data in healthy human volunteers

1. The aim of the present study was to assess the bioequivalence of two cefadroxil products, namely Ultracef (a reference product) in the form of a 500 mg capsule (produced by Bristol-Myers Squibb Laboratories, Princeton, NJ, USA) and Roxil (a test product) in the form of a 500 mg capsule (produced by Tabuk Pharmaceutical Manufacturing, Tabuk, Saudi Arabia). 2. The study was performed under US Food and Drug Administration (FDA) guidelines (http://www.fda.gov/cder) on 24 healthy male subjects. Both products were administered orally as a single dose (1 x 500 mg capsule) separated by a 1 week washout period. Following oral administration, blood and urine samples were obtained and analysed for cefadroxil concentrations using a sensitive and specific HPLC assay. 3. There were no statistically significant differences between the two products in either the mean concentration-time profiles or the cumulative urinary excretion of cefadroxil at various times. Similarly, no statistical significance was observed in the pharmacokinetic parameters reflecting rate and extent of drug absorption. The relative extent of drug absorption, assessed by calculating the area under the curve (AUC) ratio for Roxil/Ultracef for 10 h and for infinity was 0.94 with 90% confidence limits (CL) of 0.91-0.98. In agreement with serum data, the average ratio (Roxil/Ultracef) of the cumulative amount of cefadroxil excreted in urine 10 h after the dose was found to be 0.97, with 90% CL of 0.88-1.05. The CL of the AUC and cumulative urinary excretion ratios are within the FDA accepted limits for bioequivalent products (0.80-1.25). 4. These findings show that serum and urine data of cefadroxil are in agreement and indicate that Roxil (the test product) and Ultracef (the reference product) are bioequivalent in terms of the rate and extent of drug absorption.     

Concentrations of ampicillin and cefadroxil in human serum and mixed saliva following a single oral administration of talampicillin and cefadroxil, and relationships between serum and mixed saliva concentrations

The concentrations of ampicillin (ABPC) from talampicillin (TAPC) and cefadroxil (CDX) in serum and mixed saliva were assayed by the thin layer disc plate method. Talampicillin and cefadroxil (500 mg) were given by a single oral administration. The relationships between serum and mixed saliva ampicillin and cefadroxil concentrations were evaluated in the paired specimens collected from 10 different persons, respectively. The means of concentration ratios of mixed saliva to serum ampicillin and cefadroxil were 0.006 +/- 0.003 and 0.025 +/- 0.010 (mean +/- SD), respectively. Significant correlation coefficients between mixed saliva and serum concentrations were found for both ampicillin and cefadroxil, which were r = 0.78, P less than 0.001, and r = 0.67, P less than 0.001, respectively.     

Experimental studies on the influence of surfactants on intestinal absorption of drugs. Cefadroxil as model drug and sodium taurocholate as natural model surfactant: studies in rat colon and in rat duodenum

The influence of the natural bile acid surfactant sodium taurocholate (CAS 81-24-3) on colic and duodenal (i.e. the proximal third of the small intestine) absorption of cefadroxil (CAS 50370-12-2) was studied using the in situ rat gut technique, and compared with the effect of sodium lauryl sulfate (CAS 151-21-3), the most widely used synthetic anionic surfactant. Previously, the stability, compatibility, and micelle-solubilization characteristics of taurocholate were assessed in order to correct, when necessary, the absorption results. White the passive absorption rate constants (kf, h-1) determined in colon in the presence of increasing lauryl sulfate concentrations showed an asymptotic value about 7-fold higher than that of cefadroxil alone, only a 2-fold higher value was obtained in the presence of taurocholate at similar concentrations. Therefore the natural surfactant would increase the polarity of the colic absorbent membrane much less than lauryl sulfate does (about 3.5 times). The effects of taurocholate on the duodenal absorption of cefadroxil, which is the sum of a single passive process and a simultaneous carrier-mediated transport, can be summarized as follows: 1. When the working concentration of cefadroxil is far from carrier saturation (0.1 mg/ml) a slight but clear net decrease in the apparent kf value is observed in the presence of increasing concentrations of the natural surfactant (from 3.0 to 2.3 h-1) 2. When the concentration of the antibiotic in the working fluid is above carrier saturation (10 mg/ml) the picture is reversed, and a slight net increase in kf in the presence of increasing concentrations of taurocholate (from 0.8 to 1.2 h-1) is found. This means that the effect of taurocholate as a noncompetitive inhibitor of active cefadroxil transport is very much smaller than that observed with lauryl sulfate. Moreover, the increase in passive absorption relative to the synthetic surfactant is also much smaller. On the basis of allometric considerations it could be concluded that for practical purposes taurocholate does not act as a substantial absorption modifier for cefadroxil, at least in the small intestine, the main absorption site of the antibiotic. It can, however, not be considered an inert ingredient, and therefore oral administration of cefadroxil far from that of taurocholate-containing preparations, and even from lipid-rich meals should be strongly recommended.     

A pharmacokinetic comparison of cephalexin and cefadroxil using HPLC assay procedures

The pharmacokinetics of cephalexin and cefadroxil were compared following single 500 mg oral doses to 12 healthy male volunteers. Doses were administered after an overnight fast according to a crossover design. Plasma and urinary levels of both compounds were determined by HPLC procedures. Cephalexin was absorbed rapidly, achieving a mean peak plasma level of 17.5 micrograms ml-1 at 1 h, compared to 16 micrograms ml-1 at 1.8 h for cefadroxil. Elimination half-lives of cephalexin and cefadroxil were 0.7 and 1.1 h, respectively. The area under the cefadroxil plasma curve was significantly larger than that for cephalexin. However, after allowing for differences in elimination rate constants and assuming equal distribution volumes, plasma data indicated the compounds were equally well absorbed. Only 70 per cent of cefadroxil was recovered in urine compared to 87 per cent of cephalexin during the 12 h following drug administration. The therapeutic significance of the different pharmacokinetic characteristics of cephalexin and cefadroxil, if any, may be a function also of their pharmacologic activity and/or the sensitivity of the target organism.     

Cefetamet pivoxil in acute pyelonephritis: an open study

Fifty-five adult patients with acute uncomplicated pyelonephritis were investigated in an open, prospective, randomized comparative study in which 31 patients were allocated to receive 1000 mg cefetamet pivoxil twice daily (or 2000 mg once daily) and 24 to receive 1000 mg cefadroxil twice daily, given orally for 10 to 15 days. Both groups were comparable for age, sex and body weight. Clinical signs and symptoms, i.e. flank tenderness, dysuria, urgency and pyuria, subsided somewhat more rapidly with cefetamet pivoxil, while defervescence was obtained by Day 3 +/- 1 in both groups. Twenty-nine of the cefetamet pivoxil patients were assessed bacteriologically. The pathogens isolated prior to treatment were E. coli (22), Proteus mirabilis (5), P. vulgaris (1) and P. stuartii (1). All 29 patients had sterile urine at treatment end. In the 22 assessable patients in the cefadroxil group, the pathogens isolated before treatment were E. coli (17), P. mirabilis (3), and K. pneumoniae (2). Six patients had relapsed at treatment end (5 E. coli and 1 P. mirabilis). Patients were re-assessed at follow-up, usually 2 to 4 weeks after the end of treatment. Four of the 29 patients in the cefetamet pivoxil group showed relapse (3 E. coli and 1 P. mirabilis) as did a further 3 in the cefadroxil group (2 E. coli and 1 P. mirabilis). The overall therapeutic outcome was considered as successful, i.e. cure or improvement, in 89.7% of the cefetamet pivoxil patients and 72.7% of those who had received cefadroxil. Tolerability was satisfactory for both trial drugs and there were only a few mild to moderately severe adverse events reported.(ABSTRACT TRUNCATED AT 250 WORDS)     

First-derivative spectrophotometric and LC determination of cefuroxime and cefadroxil in urine

Two methods are presented for the determination of cefuroxime and cefadroxil in human urine using first (1D) derivative spectrophotometry and high-performance liquid chromatography. Cefuroxime and cefadroxil were determined by measurement of their first-derivative amplitude in 0.1 N sodium hydroxide at 292.5 and 267.3 nm, respectively in the concentration range of 2-10 microg ml(-1) for each drug. The HPLC method depends upon using a LiChrospher 100 RP-18 (5 microm) column at ambient temperature for cefuroxime and 35 degrees C for cefadroxil with mobile phases consisting of water-acetonitrile-acetic acid (85:15:0.1 v/v) at a flow rate of 1.5 ml min(-1) for cefuroxime; and 0.02 M potassium dihydrogen phosphate-acetonitrile (95:5 v/v) containing 0.003% (w/v) hexanesulphonic acid sodium salt and adjusted to apparent pH 3 with phosphoric acid at a flow rate of 2 ml min(-1) for cefadroxil. Quantitation was achieved with UV detection at 275 and 260 nm for cefuroxime and cefadroxil, respectively, based on peak area with linear calibration curves at the concentration ranges of 2-10 microg ml(-1) for cefuroxime and 5-20 microg ml(-1) for cefadroxil. The proposed methods were applied to the determination of dissolution rate for tablets and capsules containing each drug. The urinary excretion patterns as the cumulative amounts excreted have been calculated for each drug using the proposed methods.     

Intestinal transport of cefuroxime axetil in rats: absorption and hydrolysis processes

Studies were performed using three cefuroxime axetil solutions (11.8, 118 and 200 microM) in three selected intestinal segments and one cefuroxime axetil solution (118 microM) in colon of anaesthetized rats. First-order absorption rate pseudoconstants, k(ap) and effective permeability coefficients, P(eff), were calculated in each set. Absorption of cefuroxime axetil can apparently be described as a carrier-mediated transport, which obeys Michaelis-Menten and first order kinetics in the proximal segment of the small intestine and a passive diffusion mechanism in the mean and distal segments. The absorption kinetic parameters for cefuroxime axetil were obtained: Vm=0.613 (0.440) microM min-1; Km=31.49(28.31) microM and ka=0.011(0.003) min-1. Parameters characterizing degradation of the prodrug were obtained in each intestinal segment: proximal segment k(dp)=0.0049(0.0003) min-1, mean segment, k(dm)=0.0131(0.0007) min-1 and distal segment k(dd)=0.019(0.0009) min-1. Therefore, in situ intestinal absorption of cefuroxime axetil in the proximal segment of the rat in the presence of variable concentrations of cefadroxil has been investigated in order to examine the inhibitory effect of cefadroxil on cefuroxime axetil transport. The data suggest that cefadroxil and cefuroxime axetil share the same intestinal carrier.     

Absolute bioavailability and absorption profile of cyanamide in man

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral administration. Cyanamide plasma levels were determined by a sensitive HPLC assay, specific for cyanamide. After intravenous administration cyanamide displayed a disposition profile according to a two-compartmental open model. Elimination half-life and total plasma clearance values ranged from 42.2 to 61.3 min and from 0.0123 to 0.0190 L.kg-1.min-1, respectively. After oral administration of 0.3, 1.0, and 1.5 mg/kg x +/- SEM values of Cmax, tmax (median) and AUC were 0.18 +/- 0.03, 0.91 +/- 0.11, and 1.65 +/- 0.27 micrograms.ml-1; 13.5, 13.5, and 12 min; and 8.59 +/- 1.32, 45.39 +/- 1.62, and 77.86 +/- 17.49 micrograms.ml-1.min, respectively. Absorption was not complete and the oral bioavailability, 45.55 +/- 9.22, 70.12 +/- 4.73, and 80.78 +/- 8.19% for the 0.3, 1.0, and 1.5 mg/kg doses, respectively, increased with the dose administered. The models that consider a first-order absorption process alone (whether with a fixed or variable bioavailability value as a function of dose) or with loss of drug due to presystemic metabolism (with zero-order or Michaelis-Menten kinetics) were simultaneously fitted to plasma level data obtained following 1 mg/kg i.v. and 0.3, 1.0, and 1.5 mg/kg oral administrations. The model that best fit the data was that with a first-order absorption process plus a loss by presystemic metabolism with Michaelis-Menten kinetics, suggesting the presence of a saturable first-pass effect.     

Flow injection chemiluminescence determination of cefadroxil using potassium permanganate and formaldehyde system

A simple, rapid and precise flow injection chemiluminescence (FI-CL) method is proposed for the determination of cefadroxil and is suitable for application to other antibiotics containing phenolic hydroxyl groups. A possible mechanism for this selectivity is suggested. The method is based on the CL-emitting reaction between cefadroxil and potassium permanganate in sulfuric acid medium, enhanced by formaldehyde (HCHO). Under the optimum conditions, calibration graphs over the ranges of 0.05-0.8 and 1.0-10.0 microg ml(-1) were obtained. The proposed method was successfully applied to the determination of cefadroxil in pharmaceutical formulations with no evidence of interference from common excipients. The detection limit (3sigma) of this method is 25 ng ml(-1) (6.9 x 10(-8) mol l(-1)). The relative standard deviation was less than 2% for 0.4 and 4.0 microg ml(-1) cefadroxil (n = 20). The sample throughput was found to be 120 h(-1).     

Synthesis and antimicrobial activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives of cefadroxil.

Eleven new 7-[2-(dihydro-5-substituted-6-thioxo-2H-1,3,5-thiadiazine-3( 4H)-yl)-2- (4-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid derivatives were synthesized by the reaction of cefadroxil monohydrate, formaldehyde and substituted potassium dithiocarbamate. Their structures have been elucidated by spectral data and elementary analysis. The title compounds were tested for antimicrobial activity in vitro against gram-positive bacteria (Staphylococcus aureus, Streptococcus faecalis), gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and yeast-like fungi (Candida albicans, C. parapsilosis, C. stellatoidea, C. pseudotropicalis) in comparison with cefadroxil monohydrate. The activity of compounds 1 and 10 against S. aureus (MBC: 37.5 micrograms/ml) and compound 1 against E. coli (MBC: 75 micrograms/ml) were found to be the same as cefadroxil monohydrate. Compounds 1 and 10 were more effective than cefadroxil monohydrate against S. faecalis with 25 and 37.5 micrograms/ml MBC values, respectively. None of the compounds and cefadroxil monohydrate proved to be effective against P. aeruginosa (MBC: greater than 100 micrograms/ml). While cefadroxil monohydrate had no activity against yeast-like fungi, compounds 9 and 10 were significantly effective against yeast-like fungi (MFC: 37.5 micrograms/ml).     

头孢羟氨苄片的人体生物等效性研究

目的:研究2种头孢羟氨苄片的人体生物等效性。方法:将30名健康男性志愿者随机分为2组,分别交叉单剂量口服2种头孢羟氨苄片500mg,2次给药的间隔清洗期为14d。采用高效液相色谱法测定血药浓度,3p97软件计算药动学参数,以方差分析和双单侧t检验分析2种头孢羟氨苄片是否等效。结果:单剂量口服500mg受试制剂和参比制剂的Cmax分别为(32.45±6.69)、(31.27±6.85)μg·mL-1,tmax分别为(56.70±18.24)、(56.70±18.30)h,AUC0～300分别为(3209.84±538.71)、(3204.26±490.48)μg·min·mL-1。受试制剂的相对生物利用度为(104.0+10.1)%。结论:2种头孢羟氨苄片具有生物等效性。     

A PHARMACOKINETIC COMPARISON OF CEFADROXIL AND CEPHALEXIN AFTER ADMINISTRATION OF 250, 500 AND 1000 MG SOLUTION DOSES

The pharmacokinetics of cefadroxil and cephalexin were examined following single oral doses of either 250, 500 or 1000 mg to a total of 36 healthy volunteers. The volunteers were divided into groups of 12 per dose-group and solution doses of cefadroxil or cephalexin were administered after an overnight fast according to a crossover design for the cephalosporins but not for doses. Serial blood and urine samples were collected from each individual and were analyzed for cefadroxil or cephalexin using validated HPLC assays with UV detection. The individual subject plasma concentration–time data for each cephalosporin were analyzed using noncompartmental methods. Profiles for cephalexin in plasma showed sharper and higher peaks than those for cefadroxil. Although values for the peak concentrations (C_max) for cefadroxil were lower than that of cephalexin, the levels of cefadroxil in plasma and urine remained above the reported minimum inhibitory concentrations of susceptible organisms for longer period of time than those of cefalexin. The elimination half-life (t_1/2) of cefadroxil (about 2 h) was significantly longer than that of cephalexin (about 1 h). The values for C_max and AUC_0–∞ values for both these cephalosporins showed dose-proportional increase, whereas t_1/2, renal clearance (CL_R) remained independent of dose. These observations confirm that cefadroxil and cephalexin obey linear pharmacokinetics. The CL_r of both the cephalosporins were significantly higher than the average glomerular filtration rate at each dose level. The urinary recovery (% X_u) of each cephalosporin, accounted for over 80 per cent of the administered dose, and no significant differences in % X_u were observed between the two cephalosporins. These data suggest that the systemic availability of cefadroxil and cephalexin is similar at each dose level.     

头孢羟氨苄甲氧苄啶胶囊溶出度测定

目的：建立头孢羟氨苄甲氧苄啶胶囊溶出度测定方法。方法：以盐酸溶液（9→1000）为溶出介质,采用高效液相色谱法测定其溶出度。结果：头孢羟氨苄的浓度在38．6～192．8μg·ml^-1内呈良好的线性关系,r=1．0000,平均回收率为99．1％（RSD=0．3％,n=10）;;甲氧苄啶的浓度在7．8～39．0μg·ml^-1内呈良好的线性关系,r=0．9999,平均回收率为98．9％（RSD=0．5％,n=10）.结论：方法准确、简便,可作为制剂的溶出度测定方法。