The pharmacokinetics of fosfomycin, administered intravenously and orally at two different doses (20 and 40 mg/kg of body weight), was studied in seven volunteers. The elimination profile of this antibiotic, when administered intravenously, followed a two-compartment kinetic model, independent of dosage, giving an elimination half-life of 2.23 ± 0.62 h and an average total volume of distribution at steady state of 0.34 liter/kg. Peak serum levels after rapid intravenous administration of 20 and 40 mg/kg were 132.1 ± 31.8 and 259.3 ± 32.5 ,ug/ml, respectively.Peak serum levels after oral administration were 7.1 ± 1.6 and 9.4 ± 3.6 ,ug/ml for the 20 and 40 mg/kg doses, respectively. During the first 24 h after administration, an average of 80% of the intravenous doses and less than 25% of the oral doses were recovered in the urine.Fosfomycin, a broad-spectrum bactericidal agent which inhibits the cell wall synthesis of both gram-positive and gram-negative bacteria (4,8,17), was discovered in Streptomyces fradiae fernentation broths (15).Although pharmacokinetic properties of fosfomycin have been studied in humans (1, 12) after intravenous and oral administration of 250-or 500-mg doses, the pharmacokinetics of larger doses employed therapeutically have not been investigated.The work reported here was undertaken specifically (i) to describe the pharnacokinetics of single relatively larger intravenous and oral doses of fosfomycin and (ii) to utilize these pharmacokinetic data to determine patient dosage schedules and methods of administration. MATERIALS AND METHODSHuman volunteers. Seven adult male volunteers participated in this study after informed written consent had been obtained. Their ages ranged from 25 to 56 years (mean ± standard deviation, 36.3 ± 12.3 years), and their body weight ranged from 45 to 70 kg (57.9 ± 7.0 kg). Prestudy physical examination and pre-and postdrug laboratory findings were normal. No volunteer had a history of allergy to antibiotics or other drugs. None had taken any drug during the month before the investigational period.Dosage. Fosfomycin disodium (lot CS-906; Meiji Seika Research Laboratories, Tokyo, Japan) dissolved in 0.9% saline was administered intravenously at a concentration of 100 mg/ml. Fosfomycin calcium salt (lot FOMDHT 2; Meiji Seika Research Laboratories) was administered orally.Experimental design. Each of the seven volunteers received fosfomycin disodium salt intravenously over 5 min at doses of 20 and 40 mg (potency) per kg. The same volunteers also received fosfomycin calcium salt orally at doses of 20 and 40 mg (potency) per kg. The oral dose was followed by the ingestion of 100 to 120 ml of water. Treatments were randomized and delivered in a crossover fashion, with 2-week intervals separating the respective doses. Subjects fasted overnight before each study; food was also withheld for 2 h after dosage. Blood samples (5 ml each) were drawn from an arm vein at 0 (1 min after the completion of injection), 0.25, 0.5, 1, 2, 4, 6, and 8 h after intravenous administrati...

Pretreatment for 3 days with oral ofloxacin or norfloxacin had no significant effect on the disposition of a single i.v. dose the theophylline in healthy volunteers.

The effect of pregnancy on hepatic drug-metabolizing enzyme activity was investigated in nine healthy pregnant women using the ratio of 6-hydroxycortisol (6-OHF), to total 17-hydroxycorticosteroid (17-OHCS) in 24-hour urine as an index of the hepatic monooxygenase activity. The values of 6-OHF and the ratio (713 +/- 250 micrograms/d and 0.323 +/- 0.242; mean +/- SD) before delivery were significantly higher than they were during early puerperium (395 +/- 145 micrograms/d and 0.114 +/- 0.055) and approximately three months after delivery (237 +/- 67 micrograms/d and 0.066 +/- 0.034). Although the values three months after delivery were comparable to those found in the nonpregnant group (n = 10; 228 +/- 48 micrograms/d and 0.081 +/- 0.031), 6-OHF values one week after delivery were significantly higher than those observed in the control group. These observations suggest that drug-metabolizing enzyme induction may occur during pregnancy.

The effect of three new fluoroquinolones on theophylline kinetics and the urinary excretion of metabolites was studied in 5 healthy subjects (3 male, 2 female). All subjects received serial, single i.v. infusions of theophylline (aminophylline, 250 mg) over 60 min after 200 mg doses of a quinolone (enoxacin, ofloxacin, norfloxacin) every 8 h for 3 consecutive days, the quinolone being administered up to the day following theophylline administration. Pretreatment with ofloxacin and norfloxacin did not influence theophylline disposition, but theophylline clearance fell from 0.054 to 0.027 l.h-1.kg-1 in the presence of enoxacin, without a change in the apparent volume of distribution. Enoxacin, too, was the sole compound to increase the urinary excretion of theophylline (33.2 vs 43.9 mg, before vs after treatment), and significantly to decrease the excretion of 3-methylxanthine (3-MX), 1-methyluric acid (1-MU) and 1,3-dimethyluric acid (1,3-DMU) in 24-h urine samples (from 19.8 to 7.16 mg, from 28.3 to 10.3 mg and from 68.8 to 49.5 mg, respectively). The effect of the quinolones on hepatic drug metabolizing enzyme activity was investigated in each subject using the ratios of 6-hydroxycortisol to total 17-hydroxycorticosteroids and to free cortisol in 24-h urines as an index of the hepatic P-450-dependent enzyme system. No significant difference in ratio was observed between control and other treatments. It is concluded that the theophylline-enoxacin interaction was largely due to inhibition of a metabolic system other than the common hepatic P-450 system.

Anti-cancer drugs generally have immunosuppressive effects (1), which presents a serious clinical problem. Under selected conditions, cyclophosphamide (CPM) has an immunopotentiating effect on the delayed hypersensitivity reaction (DHR; 2-4). This effect has been attributable to the interruption of a feedback control to the effector T cells by B cells (2, 5) and/or by suppressor T cells (4, 5). Recently, similar phenomena have been reported in other cell-mediated (6, 7) and tumor immunities (8-10). Immunopotentiating effects of CPM appear to take place preferentially in vivo, suggesting that such effects may be due to a biological consequence of diffuse cell damage with CPM, rather than to a unique biochemical action on selected populations of lymphoid cells.The presence of naturally occurring suppressor T cells (11) and the effect of CPM on them have been reported previously (4, 12). Here, we report that anti-cancer agents other than CPM also exhibit potentiating effects on the DHR when they are administered according to schedules of current clinical anti-cancer therapy.