Mitsuyoshi Goto

Fosfomycin kinetics after intravenous and oral administration to human volunteers.

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 micrograms/ml, respectively. Peak serum levels after oral administration were 7.1 +/- 1.6 and 9.4 +/- 3.6 micrograms/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.

Effects of Enoxacin, Ofloxacin and Norfloxacin on Theophylline Disposition in Humans

SummaryThe 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.

Increased 6-Hydroxycortisol Excretion in Pregnant Women: Implication of Drug-Metabolizing Enzyme Induction

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 μg/d and 0.323 ± 0.242; mean ± SD) before delivery were significantly higher than they were during early puerperium (395 ± 145 μg/d and 0.114 ± 0.055) and approximately three months after delivery (237 ± 67 μg/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 μg/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.

Pharmacokinetics of doxorubicin and its active metabolite in patients with normal renal function and in patients on hemodialysis

The comparative pharmacokinetics of doxorubicin (DOX) were investigated in five hemodialysis (HD) and eight non-hemodialysis (non-HD) patients who were infused with a 40- to 60-mg dose of DOX at a constant rate over 30 min. A significant difference was observed in the total body clearance (Cl tot) of DOX between HD and non-HD patients. The area under the curve (AUC) for both DOX and doxorubicinol (DOXol), an active metabolite, showed increases of approximately 1.5 and 3 times in HD patients as compared with non-HD patients. Although these differences were not statistically significant (P<0.1), the mean residence time (MRT) of DOX and DOXol in HD patients showed a 2-fold increase in comparison with those in non-HD patients. Compartmental analysis indicated that the greater AUC values and longer MRT of DOX and DOXol in HD patients resulted from the lesser DOXol formation and disappearance of rate constants. As a consequence of the decrease in Cl tot for DOX and the marginal hemodialysis clearance of both DOX and DOXol, the present study suggests that the exposure to DOX and DOXol obtained in HD patients greater that achieved in non-HD patients. Careful attention should therefore be paid to HD patients receiving DOX.

Tobramycin Inactivation by Carbenicillin, Ticarcillin, and Piperacillin

The in vitro and in vivo inactivation of tobramycin by carbenicillin, ticarcillin, or piperacillin was investigated by the enzyme immunoassay method in clinically employed dosages. After the addition of an 80-mg dose of tobramycin to 4- to 5-g doses of a penicillin in 100 ml of 0.9% saline or distilled water, the degradation profile of tobramycin appeared to follow a biexponential pattern of decay. Remarkable losses (30 to 40%) of tobramycin combined with carbenicillin or ticarcillin were observed within 1 h, as compared with the later decline. The combination of tobramycin with piperacillin was least inactivating. When the admixture of tobramycin with carbenicillin or piperacillin used in the in vitro study was infused to six volunteers over 1 h, the observed maximum concentrations of tobramycin were on the average 66 and 74% for carbenicillin and piperacillin, respectively, of that observed after tobramycin alone was given. In contrast, the value obtained for tobramycin in combination with piperacillin was close to 90% of the control value. The elimination half-lives of tobramycin combined with the penicillins were slightly shorter than those of tobramycin alone, indicating that the interaction occurs even in patients with normal renal function.

Pharmacokinetics of Cis-Diammine-Dichlor-Platin in a Hemodialysis Patient

Cisplatin (CDDP) was administered to a 49-year-old dialysis female patient with advanced uterine cervical cancer. Analysis of the pharmacokinetics of CDDP in the patient with renal failure and at hemodialysis were compared with that of patients without renal impairment. CDDP at 30 mg was administered by drip infusion. The samples were ultrafiltrated and measured its concentration of both free (F-P) and total CDDP (T-P) by atomic absorption method. The effect of hemodialysis on the concentration of CDDP was analyzed. For the control, three patients without renal impairment were administered CDDP using the same method and its concentration was measured. The T-P clearance registered no difference between dialysis patients and controls, but F-P clearance in the HD patient was almost 5-fold lower than those in control patients, showing that F-P exposure to HD patients was 5-fold greater as a consequence of delayed disposition. The protein binding rate of CDDP was more gradual than that of the controls. The T-P and F-P removal rates positively correlated to the shunt side blood F-P.

Delayed disposition of adriamycin and its active metabolite in haemodialysis patients.

Recently, the number of dialysis patients has increased and their life span has become longer as a result of advances in haemodialysis technology and in supporting therapies. Due to this lengthened life span and their immunocompromised state, which is caused by renal failure, the occurrence of malignant tumours in these patients is also increasing [1]. Adriamycin (ADR) is one of the drugs used in the treatment of tumours. However, pharmacokinetic data on ADR and its active metabolite, adriamycinol (ADR-OH) [2], in haemodialysis patients do not appear to have been published. This study was conducted to compare the pharmacokinetic profiles of ADR and ADR-OH in non-haemodialysis (non-HD) and haemodialysis (HD) patients with cancer. Five HD patients [2 cases of lung cancer, 2 of malignant lymphoma and one hepatoma; 3 m and 2 f; 47-72 y (56 (11) y); 42-68 kg (56 (11) kg)] and 8 non-HD patients [3 cases of breast cancer, 2 of malignant lymphoma, and each of prostate cancer, gastric cancer, and bone tumour; 4 m and 4 f; 47-73 y (60 (9) y); 39-74 kg (55 (13) kg)], from whom informed consent had been obtained, participated in the study. They all received vincristine (VCR), cyclophosphamide (CPA), and/or 5-fluorouracil (5-FU), and cisplatin (CDDP), CPA, VCR, and/or 5-FU, respectively. Total and Direct bilirubin in the HD patient with hepatoma were within the normal ranges. ADR (Adriacin ®, Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan) 40 to 60 mg per patient was given IV over 30-min at constant rate. In the HD patients, administration was performed just after dialysis. Blood samples were collected from the contralateral arm at 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, and 43 h after the end of the first ADR infusion. In three HD patients, blood was also sampled from the catheter of the AV shunt during HD. The membrane for haemodialysis was made of cuprammonium rayon (Benberg ®, Asahi Medical, Tokyo, Japan). After centrifugation, plasma was frozen at 70°C until assayed. Plasma ADR and ADR-OH were measured by HPLC, using daunorubicin as the internal standard [Ohtsubo K, Aoyama T, 1988, unpublished data]. Briefly, the plasma containing internal standard was passed through a TOYOPAK ODS-M cartridge (TOSOH, Tokyo, Japan). ADR and ADR-OH were eluted from the cartridge with acetonitrile/100mM sodium citrate buffer, PH3.5 (30:70). This eluate was injected into the HPLC (LC-6A system, Simadzu Co., Ltd., Kyoto, Japan) equipped with a fluorescence detector (model RF-530) excitation wave length, 470 nm, emission wave length, 560 nm and a Cosmosil Packed ODS column (25 cm x 4.6 mm i.d., Nacalai Tesque Co., Ltd., Kyoto, Japan). With this method, concentrations of ADR and ADR-OH 1 ng/ml or greater in plasma could be determined. Statistical moment theory was applied to pharmacokinetic analysis [3]. The area under the curve (AUC) was calculated by the trapezoidal rule with extrapolation. Total body clearance was determined as.

Inhibitory effect of free fatty acids on plasma protein binding of disopyramide in haemodialysis patients

SummaryThe plasma (or serum) protein binding of disopyramide (DSP) in five haemodialysis patients was studied using an ultrafiltration technique. There was an increase in the free fraction of DSP in the plasma on dialysis days in comparison to the levels on interdialysis days, which was associated with an elevation of the free fatty acid levels in the plasma together with the increase of the free fraction of DSP. The inhibitory effect of free fatty acids on DSP binding in an in vitro study was enhanced in proportion to their concentrations, and was shown to be due to competition at one binding site by experiments with oleic acid as a representative displacer.Certain endogenous organic acids, such as indoxyl sulphate, 2-hydroxyhippuric acid and hippuric acid, which are characteristically elevated in chronic renal failure, scarcely affected the protein binding of DSP. The findings indicate that free DSP should be monitored in patients with elevated plasma free fatty acid levels, such as those on haemodialysis therapy.

Inhibitory effect of enoxacin, ofloxacin and norfloxacin on renal excretion of theophylline in humans

It has recently been shown that the theophyllineenoxacin interaction was mainly due to metabolic inhibition of a system other than the common hepatic P-450 activity [1]. Beckmann et al. recently reported that enoxacin inhibited the renal clearance of theophylline metabolites and, although it was not significant, the renal clearance oftheophylline tended to be lower in the presence of enoxacin [2]. The effect of co-administration of enoxacin, ofloxacin and norfloxacin with theophylline on the renal excretion of theophylline has now been examined in order to elucidate the mechanism of the theophylline-quinotone interaction in the kidney.

Plasma free fatty acids and protein binding of disopyramide during haemodialysis

SummaryThe binding of disopyramide (DSP) to plasma (or serum) proteins was determined using an ultrafiltration technique in three patients undergoing haemodialysis.An increase in the free fraction (FF) of DSP during dialysis occurred together with elevation of the free fatty acid (FFA) level in plasma. The effect of FFA on protein binding in vitro was examined using DSP- and FFA-spiked solutions containing human α1-acid glycoprotein and serum albumin. The FF of DSP rose in proportion to increasing FFA levels, supporting the in vivo observations.The findings suggest that the free concentration of DSP should be routinely monitored, especially in haemodialysis patients.