Pharmacokinetics of chlorproguanil in man after a single oral dose of Lapudrine

The pharmacokinetic parameters of chlorproguanil (Lapudrine) and its active metabolite, chlorcycloguanil, were determined in 6 healthy male volunteers after a single oral dose of 4 Lapudrine tables (80 mg). The mean maximum plasma chlorproguanil concentration was 36.7 +/- (SD) 7.9 ng/ml and was reached at 3.8 +/- 1.3 h. The chlorproguanil elimination half-life was 17.5 +/- 6.7 h and its plasma clearance was 1.28 +/- 0.12 l/h/kg. The mean whole blood to plasma ratio was 3.1 at 4 h after dosing. Chlorcycloguanil could not be quantified in plasma and whole blood at the detection limit of 10 ng/ml using a high-performance liquid chromatographic method. An excretion rate-time plot from urine data shows a rapid (t1/2 = 20 h) and a slow phase (t1/2 = 51 h) in the elimination of chlorcycloguanil. Our findings suggest that the current prophylactic regimen of chlorproguanil hydrochloride (20 mg weekly) may not be optimal in preventing infections with chloroquine-resistant falciparum malaria.     

Pharmacokinetics of mecillinam in health subjects.

Mecillinam is an amidino penicillinate derivative with a broad spectrum of activity against many gram-negative bacilli. Moreover, marked in vitro synergy against these organisms occurs when mecillinam is combined with other beta-lactam antibiotics. The purpose of this study was to determine the pharmacokinetic disposition of this antibiotic. A single dose of 10 mg/kg was administered to 12 healthy volunteers as a 15-min intravenous infusion. Multiple plasma and urine samples were collected at frequent intervals for 8 and 24 h, respectively. Plasma samples were assayed for mecillinam by using a specific high-pressure liquid chromatographic assay developed in our laboratory. Peak plasma levels ranged from 34 to 80 micrograms/ml, and after 4 h, plasma levels were 0.7 to 1.9 microgram/ml. The mean terminal plasma half-life was 51.1 +/- 8.6 min. The mean steady-state volume of distribution was calculated to be 0.23 +/- 0.04 liter/kg. The mean plasma and renal clearances were 3.5 +/- 0.4 and 2.5 +/- 0.4 ml/min per kg, respectively. The mean percentage of the dose excreted unchanged in the urine at 4 h was 67 +/- 5%; 71 +/- 6% was recovered in 24 h. Urine concentrations at 4 h were far above the minimum inhibitory concentration for susceptible gram-negative organisms.     

High-pressure liquid chromatographic analysis of BMY-28142 in plasma and urine.

A high-pressure liquid chromatographic assay was developed for the quantitative analysis of a new cephalosporin, BMY-28142, in plasma and urine. The plasma method involved protein precipitation with acetonitrile and trichloroacetic acid followed by extraction of the acetonitrile into dichloromethane. After centrifugation, the organic phase was discarded, the aqueous solution was injected into a reverse-phase column, and peaks were detected at 280 nm. The urine method involved dilution of a urine sample with sodium acetate buffer (pH 4.25) and direct injection into the high-pressure liquid chromatography system. The assay validation data indicate that the assays for BMY-28142 in plasma and urine were specific, accurate, and reproducible. The analytical methods were applied to the determination of protein binding in human serum and to a pharmacokinetic study in rats. The results of the protein-binding study indicated that BMY-28142 was 16.3% bound to human serum proteins. In the pharmacokinetic study in rats, the maximum level in plasma of 38.7 micrograms/ml was achieved at 2.33 h after administration of a subcutaneous dose of 100 mg/kg. The levels in the plasma then declined with an elimination half-life of about 0.56 h. The mean values for the steady-state volume of distribution and total body clearance were 0.46 liters/kg and 11.9 ml/min per kg, respectively. The 0- to 24-h excretion of intact BMY-28142 in urine accounted for 88.6% of the dose.     

Effect of dose on pharmacokinetics and serum bactericidal activity of mezlocillin.

Mezlocillin is subject to dose-dependent pharmacokinetics. Previous studies have examined the pharmacokinetic but not the pharmacodynamic aspects of this effect. The pharmacokinetic disposition of mezlocillin was determined in eight healthy volunteers in a randomized, crossover fashion after single infusions of 50 and 80 mg of mezlocillin per kg of body weight. Plasma and urine were assayed with a specific high-pressure liquid chromatography assay and analyzed by noncompartmental methods. Pharmacodynamic (bactericidal) effects were evaluated from serial serum bactericidal titers obtained after each dose by using the area under the bactericidal activity curve method. The mean mezlocillin total body clearance decreased from 203.6 +/- 36.2 ml/min after the 50-mg/kg dose to 171.7 +/- 42.1 ml/min after the 80-mg/kg dose (P, 0.01). The decreased clearance was reflected by a decrease in nonrenal clearance only (108.9 +/- 20.0 to 77.9 +/- 23.5 ml/min, respectively; P, 0.001). Mean areas under the curve for concentration in plasma versus time normalized to the 50-mg/kg dose were 314 +/- 73 and 375 +/- 64 micrograms X h/ml for the low and high doses, respectively (P, 0.01). No significant changes were observed in the steady-state volume of distribution or elimination half-life. Mean areas under the bactericidal activity curve were 100 +/- 77 and 244 +/- 143 for the 50- and 80-mg/kg doses, respectively. The decrease in mezlocillin clearance and the disproportionate increase in the area under the curve for concentration in plasma versus time, coupled with the observed prolonged bactericidal effects of the 80-mg/kg dose, lend support for administration of mezlocillin at a higher dose less frequently (e.g., 5 g every 8 h). Clinical trials with the higher-dose regimen are warranted to validate these observations.     

Pharmacokinetics of cefpimizole in normal humans after single- and multiple-dose intravenous infusions

The pharmacokinetics of cefpimizole (free acid equivalents of cefpimizole sodium), a broad-spectrum cephalosporin antibiotic, were determined after single- and multiple-dose 20-min intravenous infusions of 1, 2, and 4 g. The kinetics of single-dose administration of cefpimizole correspond to a two-compartment model with an average apparent volume of distribution of 20.0 +/- 3.5 liters, a distribution rate constant of 2.24 +/- 1.00 h-1, and a terminal rate constant of 0.358 +/- 0.036 h-1 (half-life, 1.9 h). The total body clearance was 118.6 +/- 20.2 ml/min. The primary route of elimination for cefpimizole was the renal route, with approximately 80% of the administered dose excreted as the parent compound. The elimination rate constant, as calculated from urinary excretion data, was 0.339 +/- 0.043 h-1, which is in close agreement with the terminal rate constant for plasma. Renal clearance of cefpimizole was 96.2 +/- 17.3 ml/min. Dose proportionality over the three dose levels was obtained from area under the plasma curve and cumulative urinary excretion data. The results of the multiple-dose study indicated that no apparent change in the distribution or elimination kinetics of cefpimizole occurred after the administration of 1-, 2-, and 4-g doses for 7 days, three times a day. The kinetics from the multiple-dose study were in close agreement with those from the single-dose study. No accumulation of cefpimizole occurred, and nondetectable levels was observed 24 h after administration of the last dose. Peaks that could be attributed to metabolites of cefpimizole were not observed during high-pressure liquid chromatographic analysis of either plasma or urine specimens.     

Pharmacokinetics of cefepime in cystic fibrosis patients.

The purposes of this study were to determine and compare the single- and multiple-dose pharmacokinetics of cefepime in patients with and without cystic fibrosis. Twelve patients with cystic fibrosis hospitalized for treatment of acute pulmonary exacerbations were studied. In addition, pharmacokinetic data for seven of the patients with cystic fibrosis were compared with those for seven age-matched control patients. The cefepime dose was 50 mg/kg of body weight (maximum, 2 g) administered as a 30-min intravenous infusion every 8 h for a minimum of 8 days. Serial plasma and urine samples, obtained after the first and last doses, were analyzed for cefepime content by a validated high-pressure liquid chromatographic assay. By standard noncompartmental analysis, the pharmacokinetic parameters ascertained were area under the concentration in plasma-time curve, elimination half-life, total body clearance, renal clearance, and volume of distribution at steady state. In addition, the maximum concentration in plasma was recorded. Mean (+/- standard deviation) results of the first dose analysis in patients with cystic fibrosis were as follows: maximum concentration in plasma, 142.6 (+/- 26.07) micrograms/ml; area under the concentration in plasma-time curve, 265.3 (+/- 114.31) micrograms.h/ml; elimination half-life, 1.8 (+/- 0.53) h; total body clearance, 127.2 (+/- 50.94) ml/min; renal clearance, 91.1 (+/- 38.86) ml/min/kg; volume of distribution at steady state, 14.1 (+/- 4.31) liters. Analysis for the last dose in patients with cystic fibrosis did not vary appreciably from these values, nor did those from the controls. Thus, it appears that the first-dose pharmacokinetics of cefepime are predictive of those at steady state. In order to consistently exceed the MIC for Pseudomonas aeruginosa for the entire dosing interval in patients with cystic fibrosis, a higher dose and/or different dosing interval compared with those used in this study may be necessary.     

Multiple-dose pharmacokinetics of ceftazidime and its influence on fecal flora.

Eight healthy volunteers each received 2.0 g of ceftazidime by constant intravenous infusion over 20 min twice daily every 12 h for 8 days. Concentrations of ceftazidime in serum and urine were measured by a microbiological assay and by high-pressure liquid chromatography. Qualitative and quantitative studies on aerobic and anaerobic fecal flora were carried out before, during, and 2 weeks after the end of treatment. The mean (+/- standard deviation) maximum drug concentration in serum at the end of the 20-min infusion (day 1) was 185.5 +/- 28.5 micrograms/ml, decreasing to 0.8 +/- 0.4 microgram/ml after 12 h. The mean recovery of drug in urine at 12 h was 71.5 +/- 12.2%. Pharmacokinetic parameters calculated on the basis of a two-compartment model were as follows: elimination half-life, 110.5 +/- 15.2 min; volume of distribution at steady state, 21.2 +/- 2.6 liters/100 kg; volume of distribution by the area method, 26.2 +/- 4.0 liters/100 kg; area under the serum concentration-time curve, 293.3 +/- 47.8 micrograms X h/ml; total body clearance, 116.4 +/- 20.3 ml/min per 70 kg; renal clearance, 82.2 +/- 15.1 ml/min per 70 kg. The agar diffusion test and high-pressure liquid chromatographic analysis showed a good correlation of results. Metabolites of ceftazidime could not be detected by high-pressure liquid chromatography in serum or urine. No accumulation of ceftazidime could be observed during the 8-day study period. Mean maximum drug levels in serum were 185.5 to 214.5 micrograms/ml, and mean trough levels were 0.8 to 1.1 micrograms/ml (days 1 to 8). No severe side effects were noted. During ceftazidime treatment, anaerobes were left intact, whereas members of the family Enterobacteriaceae could be isolated from stool in only three of eight subjects. Two weeks after discontinuation of the drug, all stool specimens contained ampicillin- and cefazolin-resistant gram-negative rods.     

Oral and intravenous pharmacokinetic profiles of doxofylline in patients with chronic bronchitis

Serum doxofylline concentrations were evaluated after solid-phase extraction by high-performance liquid chromatography following administration of 100 mg doxofylline given as a single intravenous dose over 10 min or 400 mg doxofylline given orally twice daily for 5 days in six and eight non-smoking, fasting, chronic bronchitic patients, respectively. Doxofylline possessed a very short distribution phase following intravenous administration, with a sustained elimination phase (half-life 1.83 +/- 0.37 h). After oral administration, the peak serum doxofylline concentration was 15.21 +/- 1.73 micrograms/ml and the mean elimination half-life was 7.01 +/- 0.80 h; there was a large inter-subject variability. No side-effects were experienced by the patients during the study.     

Pharmacokinetics and bioavailability of carbovir, a carbocyclic nucleoside active against human immunodeficiency virus, in rats.

Carbovir is a novel carbocyclic nucleoside which has been shown to have potent in vitro activity against human immunodeficiency virus, the causative agent of acquired immunodeficiency syndrome. Sprague-Dawley male rats were used to investigate the pharmacokinetics and bioavailability of carbovir. Six rats received carbovir (20 mg/kg of body weight) through the jugular vein, and blood samples were collected through the femoral vein 2, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 150, 180, and 240 min after the dose. Four of these rats also received a 60-mg/kg oral dose of carbovir, and a similar blood sampling schedule was followed. Whole-blood samples were prepared by solid-phase extraction, and the carbovir concentration in the samples was analyzed by reversed-phase high-pressure liquid chromatography. The profile of carbovir concentration in blood versus time after the intravenous dose was biexponential, with a very rapid distribution phase. Terminal elimination half-life was 21.4 +/- 4.37 min, and total body clearance was 55.2 +/- 13.8 ml/min per kg, which was within the range of the hepatic blood flow. The volume of distribution at steady state was 1,123 +/- 250 ml/kg. The blood/plasma ratio and the plasma protein binding of carbovir in rat blood were determined in vitro by ultrafiltration. The plasma protein binding of carbovir was only 20% and was not concentration dependent. However, the blood/plasma ratio decreased significantly as concentration increased, indicating saturable binding sites in erythrocytes. After the oral dose, the terminal half-life was 81.0 +/- 67.6 min, indicating that oral carbovir followed "flip-flop" kinetics, with absorption being much slower than elimination of the drug from the body. Oral bioavailability was 0.101 +/- 0.035. Double peaks were present in the concentration-time profile for each rat receiving the oral dose, indicating either a delay in stomach emptying of the drug or slow dissolution of precipitated carbovir in the stomach and upper small intestine.     

Pharmacokinetics and tissue penetration of fleroxacin after single and multiple 400- and 800-mg-dosage regimens.

The pharmacokinetics and suction-induced blister fluid penetration of fleroxacin following single and multiple (every 24 h for 5 days) oral administration of 400- and 800-mg-dosage regimens were studied in 12 young male volunteers. Plasma and urine samples up to 72 h were assayed by high-pressure liquid chromatography. The peak levels of fleroxacin in plasma were significantly higher after multiple dosing of 800 mg (14.3 versus 8.2 micrograms/ml; P less than 0.01) but not after the last 400-mg dose (6.7 versus 5.0 micrograms/ml). Increased elimination half-life occurred after multiple dosing of 800 mg, from 13.45 +/- 2.94 to 15.60 +/- 3.16 h (P less than 0.05). Mean peak concentrations in blister fluid were significantly different when the first (3.7 +/- 0.8 and 7.7 +/- 1.8 micrograms/ml for 400 and 800 mg, respectively) and last (5.7 +/- 0.9 and 12.3 +/- 2.1 micrograms/ml for 400 and 800 mg, respectively) doses were compared (P less than 0.01). The percentage of blister fluid (BF) penetration (AUCBF/AUCplasma, where AUC is area under the concentration-time curve) yielded values greater than 100% (range, 113.7 to 132.6%). After multiple administration of 800 mg, fleroxacin was cleared from the body more slowly: from 98.80 ml/min after a single dose to 77.72 ml/min following 800 mg every 24 h (P less than 0.01). Saturation of apparent nonrenal clearance is suggested to explain this difference. Fleroxacin was well tolerated by the volunteers.     

Pharmacokinetics of subcutaneous azidothymidine in rhesus monkeys.

The pharmacokinetics of subcutaneous bolus and continuous infusion azidothymidine (AZT) was studied in rhesus monkeys. Three animals received 100 mg/m2 as a bolus injection both intravenously and subcutaneously, with the order of administration randomly determined. Two animals received a continuous subcutaneous infusion of 25 mg/m2 per h for 12 or 24 h. AZT was measured in plasma by a reverse-phase high-pressure liquid chromatographic assay. Following intravenous bolus administration, AZT elimination was rapid, with a mean half-life of 1.2 h and a mean clearance of 318 ml/min per m2 (range, 200 to 441 ml/min per m2). The bolus subcutaneous dose was rapidly (time to peak concentration, 15 to 30 min) and nearly completely (fraction absorbed, 92%) absorbed without evidence of local tissue toxicity. With continuous subcutaneous infusion of AZT, the steady state was attained within 4 h and steady-state concentrations in plasma in the two animals exceeded 3.0 mumol/liter. No local tissue toxicity was observed at the infusion site. The subcutaneous route may be a practical alternative to intravenous administration of AZT and deserves further clinical study.     

Pharmacokinetics of Cefamandole in Patients with Renal Impairment

Cefamandole pharmacokinetics were investigated in 24 adult males with stable renal function and creatinine clearances of 0 to 139 ml/min. After intramuscular injection of 1.0 g of cefamandole, peak plasma concentrations were achieved between 1 and 2 h. Maximum plasma concentration and drug half-life increased as creatinine clearance decreased; i.e., with normal renal function the half-life was 1.49 +/- 0.10 h, and in anephrics the half-life was 11.48 +/- 1.91 h. The greatest increase in half-life occurred when the creatinine clearance was less than 20 ml/min. At these levels of renal impairment, there was significant variance in calculated half-life among patients. The maximum urine concentration and rate of cefamandole urinary excretion decreased as renal function declined. Evidence suggesting renal and nonrenal methods of drug elimination is presented. Hemodialysis resulted in increased cefamandole elimination.     

Comparative single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride in young and elderly adults

The single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride were compared in a randomized, two-period, crossover study involving six young (less than or equal to 35 years) and six elderly (less than or equal to 60 years) adults. Subjects ingested single 200-mg oral doses after an overnight fast, and serial plasma (0 to 96 h), nasal mucus (0 to 8 h), and urine (0 to 24 h) samples were collected for assay of drug concentration by electron capture gas chromatography. For both groups combined, rimantadine differed significantly from amantadine in peak plasma concentration (mean +/- standard deviation, 0.25 +/- 0.06 versus 0.65 +/- 0.22 micrograms/ml), plasma elimination half-life (36.5 +/- 15 versus 16.7 +/- 7.7 h), and percentage of administered dose excreted unchanged in urine (0.6 +/- 0.8 versus 45.7 +/- 15.7%). No significant age-related differences were noted for rimantadine. Urinary excretion (0 to 24 h) of rimantadine and its hydroxylated metabolites averaged 19% of the administered dose. The maximum nasal mucus drug concentration was similar for both drugs (0.42 +/- 0.25 versus 0.45 +/- 0.32 micrograms/g), and the ratio of maximum nasal mucus to plasma concentration was over twofold higher after rimantadine than after amantadine. These findings may in part explain the clinical effectiveness of rimantadine in influenza A virus infections at dosages that have lower toxicity than those of amantadine.     

Cilofungin (LY121019) shows nonlinear plasma pharmacokinetics and tissue penetration in rabbits.

We studied the plasma pharmacokinetics and tissue penetration of cilofungin (LY121019), a new echinocandin antifungal compound, by intermittent and continuous infusion in rabbits. Following a single intravenous dose of 50 mg/kg of body weight, the maximum concentration in plasma was 297 +/- 39 micrograms/ml, the area under the curve was 30.1 +/- 6.7 micrograms.h/ml, clearance was 30 +/- 10 ml/min/kg, volume of distribution was 0.85 +/- 0.23 liters/kg, half-life in distribution phase was 3.7 +/- 0.2 min (first 12 min postdose), and half-life in elimination phase was 12.9 +/- 0.7 min. When rabbits received cilofungin by continuous infusion (CI) at 10 mg/kg/h over 6 days, sustained concentrations in plasma of 290 +/- 56 micrograms/ml were seen, more than 50-fold higher than predicted if kinetics were linear. Similarly, at 5 mg/kg/h, high levels were also obtained. Such elevated levels in plasma would not have been predicted from the pharmacokinetic characteristics of cilofungin given as a single intravenous dose. Further pharmacokinetic study at several rates of CI suggested that cilofungin elimination follows Michaelis-Menten kinetics. Simultaneous cilofungin levels in plasma and tissue were then determined for rabbits receiving six intravenous, intermittent doses (ID) of cilofungin at 15 mg/kg every 4 min and for rabbits receiving CI as described above. After ID, the mean of the ratios of cilofungin levels in tissue to those in plasma were highest for liver and bile but very low for cerebrum and cerebellum. After CI, ratios were as much as 89 times higher than for ID and significantly greater in the brain, choroid, kidney, and bile (P less than 0.05). We conclude that following a single dose of cilofungin, the compound is rapidly cleared via first-order kinetics and does not penetrate into the central nervous system, whereas following CI, cilofungin exhibits nonlinear saturable kinetics, is slowly cleared, and significantly penetrates into central nervous system tissues.     

Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women.

Fleroxacin was administered to seven lactating women as a single oral dose of 400 mg. Plasma, urine, and milk samples were collected for up to 48 h after administration. Drug concentrations were determined by a reversed-phase high-pressure liquid chromatography method and were used for the pharmacokinetic evaluation. At approximately 2 h after oral administration, a maximum concentration of 5.6 mg/liter was determined in plasma; the area under the plasma concentration-time curve (AUC) amounted to 70.3 mg.h/liter, and the elimination half-life in the postdistributive phase was 8 h. Total systemic clearance was 97.3 ml/min, and urinary excretion was 38% of the dose within 48 h. In addition, 8.6% of the N-demethyl metabolite and 4.4% of the N-oxide metabolite were recovered from urine. In comparison with previous results obtained with healthy male volunteers, the time to reach maximum concentrations in plasma was twice as long in the nursing women, and total clearance as well as urinary elimination were reduced by 25%. In breast milk, the mean maximum concentration was 3.5 mg/liter, which was reached 2.6 h after drug administration. The elimination half-life of fleroxacin in milk was identical to that in plasma, and the AUC reached 43.3 mg.h/liter. On the basis of the comparison of the AUC in milk versus the AUC in plasma, the proportion of fleroxacin penetration into milk was 62%. The cumulative excretion in milk amounted to only 0.219 mg within 48 h. On the basis of an average daily intake of milk of a breast-fed child of 150 ml/kg of body weight, the maximum daily ingested fleroxacin dose would not exceed 10 mg. However, quinolones are known to induce arthropathy in juvenile animals, and therefore, administration of fleroxacin to breast-feeding women cannot be allowed.     

Single-dose pharmacokinetics of oral fleroxacin in bacteremic patients.

Fleroxacin is a new broad-spectrum quinolone which can be given by the oral route. The present study was designed to assess the influence of bacteremia on the pharmacokinetics of a single oral dose of fleroxacin. Thirteen patients with proven bacteremia (one or more pairs of positive blood cultures, no hypotension) were given a single 400-mg fleroxacin dose orally on two occasions while also receiving standard antibiotic therapy. The first dose was administered 12 to 36 h after the last positive blood culture was drawn (day 1), and a second dose was administered 7 days later (day 7 +/- 2) to compare the pharmacokinetics between the acute and the convalescent phases of the disease. Following each administration of fleroxacin, serial plasma samples were collected for up to 72 h and were analyzed for unchanged drug by a reversed phase high-pressure liquid chromatography technique. There were no significant changes in the following pharmacokinetic parameters (mean standard deviation) the maximum concentration of drug in serum (6.4 +/- 1.5 versus 6.7 +/- 1.9 mg/liter), the minimum concentration of drug in serum, defined as the concentration of drug in serum at 24 h postdose (3.0 +/- 1.7 versus 2.5 +/- 1.2 mg/liter), the time to the maximum concentration of drug in serum (2.3 +/- 1.4 versus 2.0 +/- 1.2 h), and the elimination half-life (19.7 +/- 8.0 versus 17.9 +/- 6.9 h). Fleroxacin clearances were compared for each individual patient. A positive correlation (R2 = 0.787) was found between the values measured on day 1 and day 7. Oral clearance of fleroxacin (CL = CL/F, where F is bioavailability was slightly, but not significantly, reduced during the bacteremic phase (oral clearance, 43.8+/- 23.5 versus 48.5 +/- 17.5 ml/min.). When compared with previous results obtained in healthy young subjects, longer times to the maximum concentration of drug in serum and elimination half-lives and higher areas under the curve were observed. This could be due to the bacteremic state, the old age of the patients (mean, 66 years), and the low renal clearance (mean calculated creatinine clearance, 71.1 ml/min). A single oral dose of 400 mg of fleroxacin provides sufficient levels in serum to cover susceptible microorganisms for at least 24 h in bacteremic patients. Renal function appeared to be the key element that had to be taken into consideration to adapt fleroxacin dosage profiles in our patient population. Bacteremia itself appeared to amplify that phenomenon, but to a much lesser extent than renal function did.     

Biliary excretion of rufloxacin in humans.

Rufloxacin is a new once-daily antibacterial fluoroquinolone with a long half-life. The aim of the present study was to evaluate the plasma and biliary kinetics and biliary and urinary excretion of rufloxacin in patients with extrahepatic cholestasis. Twelve patients with total external percutaneous transhepatic biliary drainage were given a single oral dose of 400 mg of rufloxacin. Plasma, bile, and urine samples and fractions were collected over 72 h after drug administration. Rufloxacin and its major metabolite, the N-desmethyl derivative, were measured by high-performance liquid chromatography. Maximum rufloxacin concentrations in plasma and bile (means +/- standard deviations) were 4.05 +/- 1.38 micrograms/ml and 8.24 +/- 7.16 micrograms/ml, respectively, and were reached in 4.2 +/- 3.0 h and 4.2 +/- 3.5 h, respectively. The terminal elimination half-life of rufloxacin in plasma was 45.1 +/- 13.5 h. Apparent plasma clearance was 31.3 +/- 10.5 ml/min, while biliary clearance was 0.4 +/- 0.2 ml/min and renal clearance was 12.7 +/- 6.0 ml/min. In 72 h, 0.9% +/- 0.8% of the dose given was recovered in bile and 27.2% +/- 12.0% was recovered in urine. Biliary concentrations exceeded the MICs of most common biliary tract pathogens for at least 24 h after administration. The broad antibacterial spectrum of rufloxacin and its high and prolonged biliary concentrations suggest that this drug may be useful for treatment of biliary tract infections.     

Pharmacokinetics of acyclovir suspension in infants and children.

Eighteen children from 3 weeks to 6.9 years of age were given an oral acyclovir suspension for herpes simplex or varicella-zoster virus infections. Thirteen patients who were 6 months to 6.9 years old received 600 mg/m2 per dose, and three infants and two children less than 2 years old were given 300 mg/m2 per dose. The drug was given four times a day, except to one infant who was treated with three doses a day. Among the 13 children who received the 600-mg/m2 dose, the maximum concentration in plasma (Cmax) was 0.99 +/- 0.38 microgram/ml (mean +/- standard deviation), the time to maximum concentration (Tmax) was 3.0 +/- 0.86 h, the area under the curve (AUC) was 5.56 +/- 2.17 micrograms.h/ml, and the elimination half-life (t1/2) was 2.59 +/- 0.78 h. The three infants less than 2 months of age who received the 300-mg/m2 dose had a Cmax of 1.88 +/- 1.11 micrograms/ml, a Tmax of 4.10 +/- 0.48 h, an AUC of 6.54 +/- 4.32 micrograms.h/ml, and a t1/2 of 3.26 +/- 0.33 h. The acyclovir suspension was well tolerated by young children. No adverse effects requiring discontinuation of the drug occurred.     

Pharmacokinetics of glafenine and glafenic acid in patients with cirrhosis, compared to healthy volunteers

Pharmacokinetic parameters were evaluated in 12 patients with alcoholic cirrhosis and 12 healthy volunteers after a single 400 mg oral dose of glafenine. Glafenine (G) and its major active metabolite glafenic acid (GA) were measured at regular intervals using a specific high performance liquid chromatographic method. Glafenine absorption was significantly delayed in cirrhotic patients (CP) (Tmax = 2.8 +/- 1.3 hvs 1.5 +/- 0.4 h, p less than 0.01) and was dramatically reduced in 3 patients. The large hepatic 'first pass' effect observed in healthy volunteers was markedly reduced in CP (ratio Cmax GA/Cmax G = 3.6 +/- 2.9 vs 18.9 +/- 9.8, p less than 0.001; ratio areas under the curves AUC GA/AUC G = 2.3 +/- 2.3 vs 18.2 +/- 11.2, p less than 0.001). The elimination half-life of G was prolonged in the CP (13.0 +/- 13.1 h vs 1.5 +/- 0.5 h, p less than 0.01). In CP, GA elimination half-life was increased (12.0 +/- 13.4 h vs 4.3 +/- 1.3 h, NS) but the difference did not reach statistical significance because of large variability. The significant rise of G plasma concentrations (Cmax = 2.2 +/- 2.1 mg/L vs 0.7 +/- 0.2 mg/L, p less than 0.05) and its longer half-life would lead to an accumulation if the usual dosage regimen was prescribed for CP and could result in nephrotoxicity. On the other hand, lower dosage would be ineffective because only GA is active and nephrotoxic. Hence, G should be given with great caution to CP.     

Extravascular penetration of highly protein-bound flucloxacillin.

The pharmacokinetics of intravenously administered flucloxacillin (2.0 g to five volunteers) are described. The passage of flucloxacillin to peripheral lymph and suction skin blisters was monitored. This drug was selected because the high serum protein binding of 96% offered a particularly good opportunity for the study of the impact on tissue penetration. Flucloxacillin was assayed by high-pressure liquid chromatography, and pharmacokinetics were assayed by computerized curve fitting to accepted models. Penetration of flucloxacillin to extravascular foci was rapid. After 30 min the drug concentrations were 0.5 +/- 0.3 microgram/ml in lymph and 0.9 +/- 0.7 microgram/ml in blister fluid. The peak concentration was 11.7 +/- 5.6 micrograms/ml in lymph and 4.6 +/- 1.4 micrograms/ml in blister fluid. Concentrations in urine were above 111 +/- 50 micrograms/ml throughout the 8-h monitoring period, and urinary recovery was 60.4%. The half-life was 2.1 +/- 0.9 h in serum, 1.4 +/- 0.6 h in lymph, and 11.0 +/- 4.1 h in blister fluid. The differences in half-life were significant (P less than 0.05) between serum and blister fluid but not between lymph and serum. Penetration, as represented by the mean ratios of areas under the curve, was 19.7 +/- 8.1% to lymph and 38.2 +/- 11.7% to blister fluid. The flucloxacillin distribution volume during the phase of elimination was 36.4 +/- 16.0 liters and the total body clearance was 12.9 +/- 5.5 liters. Flucloxacillin showed good tissue penetration, considering its very high serum protein binding. High flucloxacillin levels in lymph and blister fluid were explained in part by drug affinity to extravascular albumin. The major impacts of high protein binding are (i) slightly slower passage into extravascular sites, (ii) slightly later peak concentration, and (iii) levels in extravascular fluid that are persistently below those in serum.