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.

Saturable small intestinal drug absorption in humans: modeling and interpretation of cefatrizine data.

This report describes an extended compartmental absorption and transit (CAT) model to estimate saturable small intestinal absorption. This model simultaneously considers passive absorption, saturable absorption, degradation, and transit kinetics in the human small intestine. Using cefatrizine as a model drug, we demonstrated that the extended CAT model, along with intravenous pharmacokinetic parameters, was able to explain the observed oral plasma concentration-time profiles. The model predicted comparable passive and saturable absorption characteristics for cefatrizine, particularly at high dose. The predicted fraction of dose absorbed was 74% at 250 mg, 61% at 500 mg, and 48% at 1000 mg, in agreement with the reported experimental data. The simulation study showed that no single physiological factor (gastric emptying, small intestinal transit, and absorption mechanism) could account for the large variability of cefatrizine absorption observed in the literature.

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.

Mass balance approaches for estimating the intestinal absorption and metabolism of peptides and analogues: theoretical development and applications.

A theoretical analysis for estimating the extent of intestinal peptide and peptide analogue absorption was developed on the basis of a mass balance approach that incorporates convection, permeability, and reaction. The macroscopic mass balance analysis (MMBA) was extended to include chemical and enzymatic degradation. A microscopic mass balance analysis, a numerical approach, was also developed and the results compared to the MMBA. The mass balance equations for the fraction of a drug absorbed and reacted in the tube were derived from the general steady state mass balance in a tube: [formula: see text] where M is mass, z is the length of the tube, R is the tube radius, Pw is the intestinal wall permeability, kr is the reaction rate constant, C is the concentration of drug in the volume element over which the mass balance is taken, VL is the volume of the tube, and vz is the axial velocity of drug. The theory was first applied to the oral absorption of two tripeptide analogues, cefaclor (CCL) and cefatrizine (CZN), which degrade and dimerize in the intestine. Simulations using the mass balance equations, the experimental absorption parameters, and the literature stability rate constants yielded a mean estimated extent of CCL (250-mg dose) and CZN (1000-mg dose) absorption of 89 and 51%, respectively, which was similar to the mean extent of absorption reported in humans (90 and 50%). It was proposed previously that 15% of the CCL dose spontaneously degraded systematically; however, our simulations suggest that significant CCL degradation occurs (8 to 17%) presystemically in the intestinal lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Estimating human oral fraction dose absorbed: a correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds.

Based on a simple tube model for drug absorption, the key parameters controlling drug absorption are shown to be the dimensionless effective permeability, P*eff, and the Graetz number, Gz, when metabolism or solubility/dissolution is not rate controlling. Estimating the Graetz number in humans and assuming that P*aq is not rate controlling give the following equation for fraction dose absorbed: F = 1 - e-2P*w. The correlation between fraction dose absorbed in humans and P*w determined from steadystate perfused rat intestinal segments gives an excellent correlation. It is of particular significance that the correlation includes drugs that are absorbed by passive and carrier-mediated processes. This indicates that P*w is one of the key variables controlling oral drug absorption and that the correlation may be useful for estimating oral drug absorption in humans regardless of the mechanism of absorption.

[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.

Clinical pharmacokinetics of five oral cephalosporins in calves.

The minimal inhibitory concentrations (MIC) of cephalexin, cephradine, cefaclor, cefatrizine and cefadroxil for Salmonella species, Escherichia coli and Pasteurella multocida isolated previously from young calves were determined. The MIC90 values for cephalexin, cephradine and cefadroxil ranged between 3.12 micrograms ml-1 and 12.5 micrograms ml-1, whereas those of cefatrizine and cefaclor were 3.12 micrograms ml-1 and 0.78 microgram ml-1, respectively. Each drug was administered intravenously and orally to groups of pre-ruminating calves and orally to early ruminating calves. Although the pharmacokinetic characteristics of the drugs after intravenous injection were similar to other beta-lactam antibiotics, significant differences between the cephalosporins examined were found in respect of certain kinetic parameters. The drugs showed rapid absorption into the systemic circulation after oral administration to pre-ruminating calves but the elimination half-life values (t1/2 beta) varied between three hours (cefaclor and cefadroxil) and nine hours (cefatrizine). The bioavailability of the drugs was about 35 per cent of the administered dose. Co-administration of probenecid with each antibiotic caused a twofold or greater increase in peak serum drug concentrations (Cmax) but the effect on t1/2 beta was variable. Cephalexin, cephradine and cefaclor given to the ruminating calves resulted in very low serum or plasma concentrations and their use should be restricted to younger calves. Cefadroxil was found to give the highest serum concentrations in this age group but had significantly lower bioavailability when compared with the unweaned calves. Provisional oral dosage regimens were computed for each cephalosporin on the basis of the MIC data and the kinetic parameters derived from intravenous and oral drug administration.