Pharmacokinetics of cephradine administered intravenously and orally to young and elderly subjects

The pharmacokinetics of IV and oral cephradine in healthy young male and female volunteers (ages 19 to 25, n = 10) were compared to those of older individuals (ages 65 to 81, n = 9). Subjects received 1 gram of cephradine by a 5-minute intravenous (IV) infusion followed the next day by a 1-gram oral dose. Serial serum and urine samples collected over a period of 12 hours after the dose were analyzed for cephradine concentration by a microbiologic assay. After IV administration, mean serum cephradine concentrations in the elderly group were significantly higher at both 6 hours (1.52 +/- 0.41 mcg/mL) and 8 hours (0.73 +/- 0.22 mcg/mL) than in the young group at 6 hours (0.43 +/- 0.11 mcg/mL). Total systemic clearance was significantly lower (2.64 +/- 0.34 vs. 4.81 +/- 0.59 ml/min/kg) and the elimination half-life was significantly longer (1.71 +/- 0.20 vs 1.12 +/- 0.13 hours) in the elderly group (P = .0001). Systemic cephradine clearance correlated positively with creatinine clearance (r2 = 0.34, P = .0110) and negatively with age (r2 = 0.79, P = .0052). The mean volume of distribution was not significantly different between the two groups. Mean renal clearance was significantly lower in the elderly group (P = .0001), but more than 80% of the dose was excreted in the urine within 6 hours in both groups. After oral administration, the mean peak concentration and time to peak concentration did not differ between groups. The relative oral bioavailability was approximately 94% in both groups. The mean serum concentrations in the elderly were higher at both 6 and 8 hours than in the young group at 6 hours. There were no differences in pharmacokinetic parameters between male and female subjects. Because of reduced cephradine clearance secondary to an age-related decline in renal function, administration of cephradine every 8 hours, rather than every 6 hours, may be sufficient in elderly patients.     

临床输液中混浊沉淀和药液变色的现象分析

目的：分析临床输液中混浊沉淀和药液变色的原因,规范临床合理用药.方法：对临床反馈的几例在使用中出现混浊、变色的现象进行综合分析.结果：头孢唑啉和头孢匹胺宜选用0.9％氯化钠注射液为溶媒;头孢菌素类药物与喹诺酮类药物联用中间宜采用冲管或静滴其他药物;甘露醇注射液中禁加其他药物;头孢拉定和奥关拉唑不宜与酸性药物配伍或联用;头孢菌素类药物与奥硝唑-氯化钠注射液联用易发生变色.结论：应加强注射药物合理使用和规范配制的宣传,保障临床安全用药.     

Antimicrobial spectrum, pharmacology and therapeutic use of antibiotics. Part 3: cephalosporins.

Various aspects of the cephalosporin antibiotics are reviewed, including mode of action and mechanisms of bacterial resistance, antibacterial activity, clinical pharmacology, adverse reactions, and therapeutic use. There are no important therapeutic differences between the two oral agents, cephalexin and cephradine. For intramuscular injection, cephaloridine has largely been replaced by cefazolin which is equally well tolerated and not as nephrotoxic; further, cefazolin has a relatively long half-life which permits its administration three or four times daily. There are no substantial therapeutic differences among the cephalosporins most commonly used intravenously--cephalothin, cefazolin and cephapirin. However, cefazolin is administered in a lower dosage and somewhat less frequently.     

The bioavailability and pharmacokinetics of guanfacine after oral and intravenous administration to healthy volunteers

Guanfacine is a centrally acting alpha-2 adrenergic agonist. The absolute bioavailability, pharmacokinetics, and renal clearance of this antihypertensive drug were investigated in healthy male volunteers. Eighteen subjects received a single oral or intravenous dose of guanfacine 3 mg in a two-way cross-over study design. Blood samples were obtained before dosing and up to 72 hours after dosing for determination of drug levels in plasma. Additional blood samples were obtained for protein binding studies. Urine was collected and pooled for specific intervals up to 96 hours after dosing. The absolute bioavailability of guanfacine after a single oral dose was 81.1%. The elimination half-lives were 13.8 hours and 13.4 hours after oral and intravenous administration, respectively. The volume of distribution results were approximately 6 L/kg by both routes of administration. The mean plasma protein binding results were 71.6%, not influenced by plasma concentration or route of administration. The urinary recovery of guanfacine was 44.3% after oral dosing and 50% after intravenous dosing. Renal clearance of guanfacine was 50% of total body clearance and appeared to be due to a net renal tubular secretory process.     

Effect of gastrointestinal maturation on absorption of beta-lactam antibiotics.

Gastrointestinal absorption of cefazolin, which is poorly absorbed in adults, and of cephradine, which is well absorbed in adults, was studied in rats during their development. Significantly higher concentrations of cefazolin in plasma after oral administration were observed in 1- and 2-week-old rats compared with 3-week-old and adult rats. A marked difference in the absorption of cefazolin by 2- and 3-week-old rats (at weaning period) was observed. No such marked difference in the absorption of cephradine by rats of various age groups was found. With cefazolin, a similar pattern of developmental change in jejunal uptake was observed. Cortisone, which causes early maturation of the intestinal membrane, was given as a preweaning injection to 2-week-old rats. This treatment decreased concentrations of cefazolin in plasma and jejunal uptake of cefazolin. Thus, the absorption of cefazolin in 1- and 2-week-old rats seems to depend on the permeability of the immature intestinal membrane before weaning. Cephradine absorption from the intestine of 1-week-old rats became saturated and inhibited by carnosine and glycylglycine when studied by the in situ loop method. Cefazolin absorption was proportional to luminally administered doses and was not affected by carnosine and glycylglycine. A nonsaturable process for cefazolin and a saturable process for cephradine were also observed in an in vitro uptake experiment.     

Bioavailability and pharmacokinetics of phenytoin during pregnancy

Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.     

Pharmacokinetics of l-propranolol during repetitive dosing in normal and uranyl nitrate-induced renal failure rats

The effect of experimental renal failure on the intravenous and oral pharmacokinetics of l-propranolol was studied in rats. Renal failure was induced by a single intravenous injection of uranyl nitrate (5 mg/kg). Pharmacokinetic studies were carried out on the fifth day after injection of the renal toxin (renal failure group) or saline (control group). Serum concentration time course of l-propranolol was characterized after a single intravenous or oral dose as well as after five consecutive doses of the drug given at 3-hr intervals. During repetitive intravenous drug administration, steady state was reached by the second dose, i.e., within 6 hr after initiation of repetitive dosing. No significant difference in the serum concentration time course of l-propranolol was observed between control and renal failure animals. In both groups the AUC over the steady-state dosing interval was on the average 21-27% higher than the AUC after a single dose, indicating a slight decrease in the systemic clearance of l-propranolol during repetitive intravenous drug administration. An approximately two- to three-fold higher serum l-propranolol concentration was observed in renal failure animals as compared to the normal controls after both single or repetitive oral dosing. The apparent reduction in oral clearance probably reflected an inhibition of the hepatic first-pass metabolism of l-propranolol in the renal failure rat. An unexpectedly high and protracted accumulation of serum l-propranolol concentration was observed during repetitive oral drug administration. Continuing accumulation was still evident after the fifth oral dose, i.e., a period of 15 hr or approximately 10 half-lives. The mean AUC over the last dosing interval was 32.0 and 17.8 times higher than the predicted steady-state estimate based on single oral dose data for control and renal failure rats, respectively. The substantial reduction in the oral clearance during repetitive drug administration may be due to an auto-inhibition of l-propranolol metabolism.     

In vitro and in vivo evaluation of MDL 19,592, an oral cephalosporin

MDL 19,592 is a new semisynthetic cephalosporin with a good therapeutic potential against Gram-positive bacterial infections when administered orally or parenterally. In the oral treatment of benzylpenicillin-resistant Staphylococcus aureus infections in mice, MDL 19,592 was superior to cephalexin, cephradine, cefaclor, cefadroxil and cefroxadine. These in vivo results reflect the in vitro superiority expressed by MDL 19,592 over the other oral cephalosporins against staphylococci. Additionally, MDL 19,592 orally was superior to cefazolin and cephalothin administered subcutaneously and to a number of penicillinase-resistant penicillins given orally or subcutaneously in the treatment of S. aureus mouse infections. MDL 19,592 killed S. aureus cells at the same or faster rate than did cephalexin or cephradine. As compared to cephalexin, MDL 19,592 was marginally superior in vitro against Streptococcus pyogenes and Streptococcus pneumoniae. In vivo, MDL 19,592 was significantly the more effective of the two against S. pyogenes and marginally more effective against S. pneumoniae. Against Gram-negative organisms, with the exception of Haemophilus influenzae, cephalexin was the more potent of the two antibiotics both in vitro and in vivo. Administered orally to mice, MDL 19,592 was absorbed as rapidly as cephalexin with both drugs attaining similar concentrations in the blood. MDL 19,592, like cephalexin, was minimally bound by mouse serum.     

Pharmacokinetics and pharmacodynamics of procyclidine in man

The pharmacokinetics and pharmacodynamics of procyclidine (10 mg) after oral and intravenous administration were studied in six healthy volunteers. Treatment order was randomised and the study was placebo-controlled and conducted blind. After oral dosing the mean peak plasma concentration was 116 ng/ml and mean bioavailability was 75%. After both oral and intravenous dosing the mean values for the volume of distribution, total body clearance and plasma elimination half-life of procyclidine were in the order of 1 l/kg, 68 ml/min and 12 h respectively. Autonomic effects were maximal within 0.5 h of intravenous administration and at about 1-2 h after oral dosing. Significant effects on pupil diameter, visual near point, salivary secretion and heart rate occurred after intravenous treatment and similar but less marked effects occurred after the oral dose. Significant autonomic effects were still detectable 12 h after both forms of treatment.     

Comparative pharmacodynamics and clinical pharmacokinetics of phenoxymethylpenicillin and pheneticillin.

In this study the antimicrobial effects of phenoxymethylpenicillin (PM) and pheneticillin (PE) in vitro and in an experimental animal infection model were compared as well as the pharmacokinetic properties of both drugs in patients. For the inhibitory effect of PM on short-term (3 h) growth of S. aureus in vitro, this drug was 2.13 times more potent than PE. The protein binding of both drugs was similar (78-80%). The potency ratio of PM to PE against S. aureus in an experimental mouse-thigh infection was only 1.25 to 1. This is explained by the difference in the AUC after subcutaneous administration of PM (0.47 mg 1(-1) h) and PE (0.92 mg 1(-1) h). The plasma clearance after intravenous administration of PM was 476.4 ml/min and that of PE was 295.1 ml/min; the plasma clearance of both drugs was strongly correlated with the creatinine clearance. The volume of distribution in the steady state of PM was 35.41 and that of PE 22.51. In 10 patients, the absorption after oral administration of PM as the acid was 48% and that of the potassium salt of PE was 86% of the dose. From the present results it can be concluded that a difference in effectiveness of different formulations of PM and PE would depend entirely on differences in absorption.     

Pharmacokinetic interaction between ϵ-acetamidocaproic acid (AACA) and cimetidine in indomethacin-induced acute gastric ulcer and control rats: inhibition of active renal secretion of AACA by cimetidine

After both the intravenous and oral administration of zinc acexamate [ZAC; ion-pairing between zinc and ?-acetamidocaproic acid (AACA)] and cimetidine together, the areas under the curve (AUCs) of AACA were significantly greater [by 28.2 and 98.9% after the intravenous and oral administration, respectively, for control rats and 13.5 and 16.9% for indomethacin-induced acute gastric ulcer (IAGU) rats, respectively] than those of ZAC alone due to the significantly slower renal clearance (CL(R)). The significantly greater AUCs of AACA after both the intravenous and oral administration of ZAC and cimetidine together in control and IAGU rats could have been due to the inhibition of active renal tubular secretion of AACA by cimetidine. After the intravenous and oral administration of both drugs together, the AUCs of cimetidine in control and IAGU rats were not different compared with those with cimetidine alone.     

Pharmacokinetics of FK027 in rats and dogs

The pharmacokinetics of FK027, a new oral cephalosporin, were investigated in rats and dogs and compared with those of cefaclor, cephalexin and amoxicillin. Upon oral administration to either rats or dogs, FK027 produced higher and more sustained serum levels than the reference drugs, hence a longer half-life. After both oral and intravenous administration, the half-life of FK027 in dogs was approximately three fold that in rats. Although the concentrations of FK027 in rat kidney, liver and spleen were lower than those of cephalexin and amoxicillin, they were sustained similarly to the serum levels. The 24-hour urinary and biliary recovery rates of FK027 in rats after oral dosing with 100 mg/kg were 34.1 and 21.9%, respectively. The urinary excretion of FK027 was significantly lower than that of the reference drugs, however, the biliary excretion was higher. In dogs, 23.4 and 0.2% of the given dose of 40 mg/kg of FK027 was excreted in the 24-hour urine and bile, respectively. Bioavailability of FK027 after oral dosing was 38% in rats and 47% in dogs, as calculated from intravenous data. Binding of FK027 to serum protein in all species was the highest of the test drugs: 63% for human, 93% for dog, 61% for rat serum.     

Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects

OBJECTIVE: The pharmacokinetics and lymphocyte responses to the immunomodulator fingolimod (FTY720) were characterized after oral and intravenous administration. METHODS: In this randomized, two-period crossover study 11 evaluable healthy subjects received single doses of fingolimod 1.25 mg orally and 1 mg intravenously infused over 2 h. The pharmacokinetics of fingolimod, blood lymphocyte counts and heart rate were characterized for 28 days after each dose. RESULTS: After oral administration, Cmax was 1.1+/-0.2 ng/ml occurring at 12 h postdose and the AUC was 201+/-31 ng.h/ml. After intravenous infusion, Cmax was 4.9+/-0.8 ng/ml, AUC was 175+/-50 ng. h/ml, clearance was 6.3+/-2.3 l/h and distribution volume was 1199+/-260 l. The oral/intravenous ratio of dose-normalized AUCs was 0.94 (95%CI: 0.78-1.12). The pharmacologically active metabolite fingolimod-phosphate was quantifiable near its peak after oral administration but not after intravenous administration. The mean lymphocyte nadir occurred on day 1 and was 35% lower after oral (0.74x10(9)/l) than after intravenous (1.15x10(9)/l) administration. Lymphocytes recovered to the normal range by day 15 for both treatments. The mean heart rate nadir occurred 3-4 h postdose and was 11% lower after oral administration (47 bpm) versus intravenous administration (53 bpm). CONCLUSIONS: Average systemic exposure to fingolimod was similar after oral and intravenous administration. However, the acute decrease in lymphocyte counts was weaker after intravenous administration, likely because of lower blood levels of the active metabolite fingolimod-phosphate compared with oral administration.     

Diuretic effect and disposition of furosemide in cystic fibrosis

Summary The pharmacodynamics and kinetics of single oral and intravenous doses of furosemide were studied in 9 patients (mean age 18.5 y) with cystic fibrosis.The diuretic effect of furosemide lasted for 6 h after oral administration and 2 h following intravenous injection of the drug.The patients with cystic fibrosis had a more pronounced diuretic response both to the oral and intravenous treatments than that reported in normals. Furosemide caused a marked decrease in urine pH for 5 h following the oral dose and between the 2nd and 3rd h after i.v. injection. The baseline nocturnal urine flow rate in 7 of the 9 patients given furosemide orally was increased by 30.6% compared to that reported in healthy subjects.The bioavailability of furosemide, its mean absorption rate and the mean plasma and urinary elimination half-lives both of the oral and the intravenous drug were similar to those reported in normal subjects. The patients with cystic fibrosis showed, however, about double normal mean total clearance after both the oral and i.v. treatments, and its renal clearance was almost half the plasma clearance. Nonrenal clearance was markedly increased in the patients, which agreed with a considerable decrease in the renal excretion of the drug. The mean apparent volume of distribution was also markedly increased compared to data in the literature. Oral furosemide resulted in a moderate increase in haematocrit and haemoglobin levels in 7 of 9 patients with cystic fibrosis and marked hypokalemia developed in 6 of the 9 patients 6 h after dosing. Pulmonary function tests performed at that time were changed in an inconsistent manner. The sweat test was significantly perturbed in those subjects, although the concentration of chloride in sweat did not fall below 60 mEq/l in any of the sweat samples tested.     

Bioavailability of metoprolol in young adults and the elderly,with additional studies on the effects of metoclopramide and probanthine

The plasma concentration curves and urinary excretion of oxmetidine after administration of single i.v. (100 mg) and oral (200 mg) doses have been studied in 11 patients with peptic ulcer disease. The mean bioavailability of the drug was 70% (range 53-91%). After intravenous administration, the mean plasma t 1/2 beta was 3.0 h, the mean apparent volume of distribution 0.7 l/kg, the mean total plasma clearance 12.3 l/h and the mean plasma renal clearance was 0.7 l/h. Following intravenous and oral administration an average of 6% and 3%, respectively, of unchanged drug was found in the urine. The plasma concentration curve after oral administration in most patients exhibited two maxima, with peak concentrations appearing between 45 and 210 min after dosing.     

The pharmacokinetics of intravenous and oral sulpiride in healthy human subjects

Summary The pharmacokinetics of sulpiride was studied in 6 healthy volunteers after intravenous and oral (tablets) administration of 100 mg. An open two- and in two subjects a three-compartment model was applied following intravenous administration. The average total distribution volume during the terminal slope was 2.72±0.66 l/kg and total systemic clearance was 415±84 ml/min. The serum half-life of the terminal slope following intravenous administration averaged 5.3 h (range 3.7–7.1 h) according to the two-compartment model. In two subjects the half-lives were 11.0 and 13.9 h when the three-compartment model was applied. Determination of urinary excretion rates of unchanged sulpiride indicated a half-life of 7.15 h. Following intravenous administration, 70±9% of the dose was recovered unchanged in urine within 36 h; the mean renal clearance was 310±91 ml/min. Sulpiride was absorbed slowly, with peak concentrations appearing between 3 and 6 h after oral administration. The recovery of unchanged drug in urine following oral administration was 15±5% of the dose, with a mean renal clearance of 223±47 ml/min. The bioavailability determined from combined plasma and urine data was only 27±9%. The low bioavailability was probably due to incomplete absorption.     

Physiologically based pharmacokinetic model for beta-lactam antibiotics I: Tissue distribution and elimination in rats

The disposition characteristics of beta-lactam antibiotics in rats were investigated, and a physiologically based pharmacokinetic model capable of predicting the tissue distribution and elimination kinetics of these drugs was developed. Protein-binding parameters in rat serum were determined by equilibrium dialysis. Linear binding was found for penicillin G, methicillin, dicloxacillin, and ampicillin; however, nonlinear binding was observed for penicillin V and cefazolin. After intravenous bolus dosing, cefazolin was recovered almost completely in urine and bile, while for the penicillins, penicilloic acid was found to be the major metabolite. Biliary excretion of cefazolin followed Michaelis-Menten kinetics, and no significant inhibition of urinary secretion was observed after probenecid administration. The renal clearance of unbound drug was 0.82 ml/min with a reabsorption ratio (R) of 0.22. Tubular secretion was inhibited for the penicillins by probenecid plasma concentrations of 50 micrograms/ml, resulting in an R-value of 0.32. Erythrocyte uptake, serum protein binding, and tissue-to-plasma partition coefficient (Kp) were measured. Theoretical Kp values were calculated and found to be in good agreement with the Kp values for three of the antibiotics. Plasma and tissue concentrations (lung, heart, muscle, skin, gut, bone, liver, and kidney) were measured as a function of time at various doses for inulin and cefazolin in rats after an intravenous bolus dose, and were found to be in reasonable agreement with concentrations predicted by the model. These correlations demonstrate that the proposed model can accurately describe the plasma and tissue contributions of inulin and cefazolin in the rat and suggest that this model could have utility in predicting drug distribution in humans.     

An in vivo-in vitro study of cefepime and cefazolin dialytic clearance during high-flux hemodialysis

STUDY OBJECTIVES: To assess the influence of in vitro and in vivo hemodialysis with a new high-flux dialyzer on the clearance of cefazolin and cefepime; to assess the correlation of in vivo dialytic clearance of these antibiotics with blood flow rate; and to assess the correlation between in vitro and in vivo dialytic clearances of these antibiotics. DESIGN: Prospective, open-label, dialysis clearance study. SETTING: A tertiary-care, university health science center. PATIENTS: Five adults who received high-flux hemodialysis 3 times/week. Intervention. For the in vivo experiment, patients received a single intravenous infusion of cefazolin 1 g and cefepime 1 g before dialysis and then underwent a modified hemodialysis session. For the in vitro experiment, a buffered simulated plasma water (SPW) solution containing cefazolin and cefepime was used. Hemodialysis for both experiments was performed with use of a new high-flux polysulfone dialyzer. MEASUREMENTS AND MAIN RESULTS: Cefazolin and cefepime dialytic clearances were determined at blood and/or SPW flow rates of 100, 200, 300, and 400 ml/minute after a 15-minute equilibration period. The degree of correlation of in vitro and in vivo clearances with blood flow rate was determined. Cefepime dialytic clearance increased proportionally with blood flow rate (p<0.01), reaching a maximum mean +/- SD value of 178.9 +/- 24.3 ml/minute at a blood flow rate of 400 ml/minute. Cefazolin dialytic clearance ranged from a mean +/- SD of 42.3 +/- 7.7 to 52.7 +/- 16 ml/minute; no significant correlation was noted between blood flow rate and dialytic clearance. In vitro cefazolin and cefepime dialytic clearances increased proportionally with SPW flow rate (p<0.05). After adjusting the in vitro cefazolin and cefepime dialytic clearances based on their degrees of protein binding, the correlation between the in vitro and in vivo cefepime dialytic clearances was significant (r(2)=0.91, p=0.04), but no significant correlation was noted between the in vitro and in vivo cefazolin clearances (r(2)=0.61, p=0.22). CONCLUSION: The in vivo hemodialysis clearances of cefepime and cefazolin with the new high-flux polysulfone dialyzer used in this study are markedly higher than values reported with conventional dialyzers but similar to values observed with other high-flux hemodialyzers. The in vivo dialytic clearance of cefazolin was significantly lower than the in vitro values, most likely due to cefazolin's high degree of protein binding. These results highlight the limitation of directly applying in vitro data to clinical situations.     

Absolute bioavailability of testosterone after oral administration of testosterone-undecanoate and testosterone

The plasma levels of testosterone (T) were measured after oral administration of 25 mg T and 40 mg testosterone-undecanoate (TU) in a group of young women by a specific radioimmunoassay. Plasma levels were compared to those after intravenous administration of 1.5 micrograms testosterone/kg to another group of young women for determination of absolute bioavailability. Due to the high metabolic clearance rate of 24.5 ml/min/kg absolute systemic availability of free testosterone was calculated to 3.56 +/- 2.45%. Oral administration of testosterone undecanoate leads only to an absolute testosterone bioavailability of 6.83 +/- 3.32%.     

Antimicrobial agents in rats. II. Serum levels of oral cephalosporins.

Cephalexin, cephradine and 7 beta-(D-2-amino-2-[(1,4-cyclohexadienyl)-acetamido])-3-methoxy-3-cephem-4-carboxylic acid (CGP 9000) were tested for their pharmacokinetic behaviour in rats. The cephalosporin serum concentrations were determined at certain times after oral administration of 150 mg/kg by the agar-well-diffusion method. The experiments revealed that the serum levels of cephalexin and cephradine did not differe essentially from one another. They maintained maximum serum concentrations of 30 microgram/ml to 40 microgram/ml during the first hour and than declined with a half-life of 2.5 h. CGP 9000 reached peak concentrations 60 to 90 min postdose and was eliminated with a half-life of 3.5 h. The area under the curve was double as large as those of cephalexin and cephradine. This may be a reason of favourable results in experimental chemotherapy with CGP 9000.