Pharmacokinetics of oral cefatrizine in pregnant and non-pregnant women with reference to fetal distribution.

OBJECTIVE: To investigate the effect of gestation on the pharmacokinetics of orally administered beta-lactams, choosing cefatrizine as the model antibiotic. SETTING: A tertiary teaching hospital. DESIGN: Prospective study. METHODS: In 20 women with affected fetuses, 17 by beta-thalassemia major and 3 with congenital malformations, termination of gestation between 19 and 24 weeks was induced by intra-amniotic administration of prostaglandin F(2)(alpha). Pharmacokinetics of cefatrizine in maternal and fetal blood were studied after the administration of three 1 g doses of oral cefatrizine, every 12 h. Twenty female non-pregnant volunteers consisted the control group. RESULTS: Gestation was found to decrease substantially both cefatrizine oral bioavailability and maximum serum plasma concentration (42.8 and 44.5%, respectively) but increased elimination half-life. This effect can be attributed to a substantial increase of the apparent volume of distribution of cefatrizine in relation to a moderate increase of clearance that occurs during pregnancy. Fetal serum cefatrizine levels were lower for the first few hours after administration and then exceeded the corresponding maternal ones. CONCLUSIONS: Our results indicate that gestation decreases the oral bioavailability of cefatrizine. A delay in the maternal drug elimination compared to non-pregnant controls was more pronounced in the fetus.

Simultaneous determination of cefatrizine and clavulanic acid in dog plasma by HPLC.

A rapid and specific high-performance liquid chromatographic method was developed and validated for the simultaneous determination of cefatrizine and clavulanic acid in the plasma of beagle dog. The sample pretreatment procedure involved reaction of clavulanic acid with 1,2,4-triazole, which readily produced a derivative with its maximum UV absorption at 314 nm. This derivative was separated in a reverse-phase C-18 column without being interfered by other components present in plasma. Cefatrizine, however, was not derivatized and, therefore determined directly at 269 nm. Sulfanilamide was used as an internal standard. The retention times of sulfanilamide, the derivative, and cefatrizine were, 3.5, 4.9, and 6.0 min, respectively. The assay showed linearity from 2 to 100 microg/ml for cefatrizine and from 1 to 50 microg/ml for clavulanic acid. Precision expressed as R.S.D. ranged from 4.2 to 18.2% for cefatrizine and 5.5 to 15.8% for clavulanic acid. Accuracy ranged from 97.9 to 120% (lower limit of quantitation) for cefatrizine and from 97.7 to 119.2% for clavulanic acid. Extraction efficiencies for cefatrizine, clavulanic acid, and internal standard from dog plasma averaged 79.8+/-5.8%, 84.8+/-6.2%, and 89.0+/-3.8%, respectively. This method was employed successfully to follow the time course of the concentration of cefatrizine and clavulanic acid in beagle dogs following oral administration of cefatrizine and clavulanic acid.

Dose dependency in the gastrointestinal absorption of cefatrizine: correlation between in vivo and in situ.

We evaluated the dose-dependent (saturable) gastrointestinal absorption of cefatrizine, an aminocephalosporin transported by peptide carriers, in rats by a physiological mechanism-based approach to clarify its absorption characteristics and to examine the in vitro (in situ)-in vivo correlation in intestinal transport. With an increase in oral dose (mumol/5 ml/kg) from 5 (low) to 50 (high), the intestinal absorption rate constant (ka), which was estimated by analysis of gastrointestinal disposition, decreased markedly, from 0.301 to 0.056 min-1. This decrease was ascribable to the saturability of intestinal membrane transport, of which the concentration dependency in the perfused intestine was similar in extent to the dose dependency in ka. However, the apparent absorption rate constant (ka'), which was estimated by analysis of plasma concentrations after oral administration, decreased only modestly from 0.037 to 0.023 min-1. This was associated with the result that, at the low dose, ka' was far smaller than ka and comparable with k(g) (gastric emptying rate constant), suggesting gastric emptying-limited absorption. At the high dose, where intestinal cefatrizine absorption was less efficient, ka' was closer to ka than k(g). It was also observed that the bioavailability was close to unity, independent of dose, suggesting that the intestinal transit time is long enough to achieve complete absorption, even at the high dose, where intestinal cefatrizine absorption is less efficient. Thus, it was found that the effect of saturability in the intestinal transport of cefatrizine is apparently attenuated in its overall gastrointestinal absorption because of the involvement of gastric emptying and intestinal transit time as additional physiological factors to define absorption. It was also found that a scaling factor is required to correlate the intestinal membrane transport between in vitro (in situ) and in vivo, though this remains to be verified to be utilized for developing oral drug delivery strategies and optimizing oral drug therapy.

Theoretical model for both saturable rate and extent of absorption: simulations of cefatrizine data.

A pharmacokinetic model incorporating saturable rate of absorption of the Michaelis-Menten type was recently developed to fit cefatrizine (CFZ) plasma concentrations with time following oral administration of 500-mg capsules to humans. This model (MM) was statistically superior to models incorporating either first-order or zero-order absorption. However, the MM model does not predict the reduction in extent of absorption with dose observed in vivo. In this study, a model is proposed in which a time constraint, delta t, is added to the MM model. This new model (MM-delta t) is tested with data following doses of 250, 500, and 1000 mg of CFZ. When delta t is set to 1.5 hr, the predicted relative changes with dose in bioavailability, F, peak plasma concentration, Cmax, the time at which the peak concentration occurs tmax, and the mean absorption time, MAT, are generally in good agreement with the experimental data. The time interval of 1.5 hr is compatible with passage by a limited region within the small intestine where drug is absorbed by a facilitated transport mechanism. Influence of each absorption model parameter (Vmax, Km, and delta t) on total area under the concentration versus time curve (AUC), F, Cmax, and tmax, is assessed by simulation. The MM-delta t model is able to summarize the nonlinerity observed in both rate and extent of absorption.

Pharmacokinetics of oral cefatrizine in patients with impaired renal function.

The pharmacokinetics of cefatrizine was studied in 15 patients with various degrees of renal impairment, after single oral administration of 500 mg. Cefatrizine elimination was reduced in parallel to renal function, as indicated by the significant correlations between apparent clearance (Cl/F) and creatinine clearance (Clcr), and between renal clearance (Clr) and creatinine clearance (Clcr). In patients with totally impaired renal function, the residual clearance (Cl/F) was 63 ml.min-1 per 1.73 m2. Comparisons with previously published data indicate that the apparent volume of distribution (V/F) of cefatrizine was lower in patients with impaired renal function than in young healthy volunteers, leading to increased peak concentrations (Cmax), but there was no relationship between V/F and Clcr. In patients with totally impaired renal function, the upper limit of cefatrizine elimination half-life was estimated to 5.5 h. The clinical significance of pharmacokinetic modifications observed in renal disease patients may only be realized through integration of pharmacodynamic characteristics of cefatrizine. The observed increase in Cmax and the lengthening of t1/2 could suggest a reduction of dosing frequency in patients with severe renal impairment.

[Pharmacokinetics of cefatrizine administered in repeated doses]. / Pharmacocinétique de la céfatrizine administrée en doses répétées.

Twelve healthy volunteers received cefatrizine orally at doses equal to 500 mg every 12 h for 5 days. Cefatrizine was assayed by high performance liquid chromatography in plasma and urines collected after the first and/or the last administration. Cefatrizine absorption was rapid; its peak plasma level was reached at time 1.79 +/- 0.07 h following the first dose, it was equal to 7.37 +/- 0.31 micrograms.ml-1. Its apparent elimination half-life was equal to 1.50 +/- 0.05 h, it explains the lack of accumulation with time during multiple administrations every 12 hours. Comparisons between peak plasma concentration and area under curves following the first and last dosing showed significant (p less than 0.01) but weak (close to 15%) reduction of these 2 parameters with time which could be explained by a slight reduction of cefatrizine absorption with time. In conclusion, cefatrizine does not accumulate when administered repeatedly at a dose equal to 500 mg every 12 h in young adult, and its pharmacokinetics is virtually linear with time.

Stability of cefatrizine in aqueous solution and in sera.

Cefatrizine (SK & F 60771; BL--S640), like most other phenylglycine-type cephalosporins, has a tendency to lose potency in aqueous solutions and in normal sera even at low temperatures. Cefatrizine can be stabilized during storage by sodium metabisulphite (Na2S2O5), a reducing agent partially in tap water, better in deionized water, and to a lesser degree in citric acid-phosphate buffer (pH 6). Although this partial stabilizing effect of sodium metabisulphite is temperature-dependent, storage at 4 degrees C gives better results than storage in the frozen state (-20 degrees C). In these aqueous solutions and in sera, the potency of cefatrizine can be preserved even at room temperature for up to four weeks by the addition of 0.1 ml of 2 N hydrochloric acid to each 2 ml of aqueous solutions or sera.

Determination of cefatrizine levels in blood, tonsils, paranasal sinuses and middle ear.

Levels of cefatrizine, a new oral cephalosporin, were determined in blood and in tonsils, paranasal sinus secretions and middle ear exudates from 18 patients with acute infections at these sites. Three and six hours after administration of 500 mg cefatrizine satisfactory levels of the antibiotic were found at all the sites examined. Levels in the tonsils and middle ear were higher than those in blood, while lower levels were recorded in nasal secretions.

Determinations of tissue levels of cefatrizine in blood, lungs and bronchi.

A study was carried out in 12 patients, divided into two groups of 6, to determine tissue levels of cefatrizine in lung (group I) and bronchial secretions (group II) following a single oral dose of 500 mg. In group I, specimens of blood and lung tissue were collected after 2 h from one subgroup of 3 patients and after 3 h from the other subgroup of 3. Average levels were 8.5 and 7.0 mcg/ml for blood and 1.2 and 1.4 mcg/ml for lung tissue respectively. In group II blood and bronchial secretion concentrations were evaluated at the 2nd, 3rd and 6th hours from administration. Average values were 9.1 and 7.7 mcg/ml in blood at 2h and 3h respectively, whereas the average bronchial secretion concentration at the 3rd hour was 10.4 mcg/ml in the first subgroup. In the second subgroup the mean level in blood collected at the 2nd hour was 8.9 mcg/ml, and 2.5 and 4.1 mcg/ml respectively in blood and bronchial secretions at the 6th hour. Cefatrizine levels in bronchial secretions were higher than those in blood at both the 3rd and the 6th hour from administration: this kinetic peculiarity of the drug will doubtless play an important role in the therapeutic efficacy of cefatrizine.

Quantitative liquid chromatographic determination of cefatrizine in serum and urine by fluorescence detection after post-column derivatization.

A fast, specific and sensitive high-performance liquid chromatographic procedure for the determination of cefatrizine, an orally active cephalosporin, in serum and urine is proposed. The drug is determined by the internal standard method, using cephradine as the internal standard. The separation is carried out on a reversed-phase column, filled with octadecylsilane chemically bonded microparticles. The eluent is a mixture of acetonitrile with 0.025 M sodium phosphate buffer (pH 7). Quantitation is effected by fluorescence detection of the fluorophores formed after post-column derivatization with fluorescamine in a packed-bed reactor. The chromatographic conditions and the conditions for the post-column derivatization are discussed. The method has been applied to serum and urine samples, which were analysed after deproteinization with trichloroacetic acid and injection of the clear supernatant. The accuracy and reproducibility of the procedure were investigated by the determination of the cefatrizine content in spiked serum and urine samples.

Determination of cefatrizine in serum and urine by reversed-phase high-performance liquid chromatography.

A fast and simple high-performance liquid chromatographic procedure for the determination of cefatrizine, an orally active cephalosporin, in serum and urine is proposed. Reversed-phase liquid chromatography on the octoadecylsilane chemically bonded microparticulate packing, using methanol in 0.03 M sodium phosphate buffer (pH 5) as eluent, was used to separate and quantitate the antibiotic. The samples were analysed after deproteinization with trichloroacetic acid and injection of the clear supernatant. The accuracy and reproducibility of the procedure were investigated by determination of the cefatrizine content in spiked serum and urine samples, using cephradine as the internal standard.