Takayoshi Oguma

Transport Characteristics of Ceftibuten, a New Oral Cephem, in Rat Intestinal Brush-Border Membrane Vesicles: Relationship to Oligopeptide and Amino β-Lactam Transport

Ceftibuten undergoes H+-coupled uphill transport across rat small intestinal brush-border membrane vesicles. The effects of amino acids, peptides, folate, and β-lactams on the uptake of ceftibuten were examined. Uptake of ceftibuten was competitively inhibited by dipeptides or tripeptides. A counter-transport effect on ceftibuten uptake was observed in the vesicle preloaded with these peptides, and the transport was temporarily against a concentration gradient (overshooting). On the other hand, ceftibuten uptake was not changed by amino acids and a tetrapeptide. Therefore, ceftibuten is predominantly transported via the oligopeptide transport system in the brush-border membranes. The relationship of ceftibuten transport to folate and other oral antibiotics was also investigated. Cyclacillin, cephradine, and cefadroxil exhibited both inhibitory and countertransport effects, but folate, cefaclor, and cephalexin showed only a slight inhibitory effect. As the transport of cefaclor showed no uphill uptake in the presence of a H+ gradient and its H+ stimulated uptake was small, a H+ gradient-independent carrier-mediated system seems to participate in its transport. These findings suggest that two different carrier-mediated transport systems, H+ gradient dependent and independent, may exist for oral cephems.

Transport characteristics of ceftibuten (7432-S), a new oral cephem, in rat intestinal brush-border membrane vesicles: proton-coupled and stereoselective transport of ceftibuten.

The transport characteristics of ceftibuten in rat intestinal brush-border membrane vesicles were investigated by a rapid filtration technique. Ceftibuten uptake was markedly stimulated by an inwardly directed H+ gradient (pH 7.5 inside, pH 5.5 outside) in comparison with that in the absence of a H+ gradient. The uptake at 30 sec was four times greater than that observed at equilibrium (overshoot phenomenon), while the H+ gradient-stimulated uptake of ceftibuten was markedly reduced in the presence of FCCP, a protonophore. These results suggested H+-coupled uphill transport of ceftibuten. In contrast, an inwardly directed Na+ gradient had no effect on ceftibuten uptake. The valinomycin-induced K+ diffusion potential (inside positive) significantly stimulated the ceftibuten uptake, suggesting net transfer of the negative charge. In contrast to the cis-isomer ceftibuten, the trans isomer of ceftibuten is not readily absorbed from the intestine, and its uptake was found not to be affected by a H+ gradient. Since the lipophilicity of the trans isomer is similar to that of ceftibuten, the uptake process appears to be stereoselective. The initial uptake of ceftibuten and its analogue cefaclor was concentration dependent under a H+ gradient. The apparent Km value was 0.2 mM for ceftibuten and 3.0 mM for cefaclor.

A Novel Pharmacokinetic Method for Analysis of Placental Transfer of Latamoxef in Humans

SummaryA novel pharmacokinetic method was developed for analysing the behaviour of a drug in tissues. The absolute transfer ratio of a drug to a tissue was defined using the pharmacokinetic parameters obtained by this method. Composite data of latamoxef (moxalactam) concentration in maternal blood, umbilical cord blood and amniotic fluid following a 2g intravenous injection to pregnant women at delivery were analysed by this method to study the drug behaviour in pregnant women, fetuses and amniotic fluid.Latamoxef kinetics in pregnant women at full term were generally similar to that in previously reported healthy subjects. The concentration of latamoxef in umbilical cord blood peaked about 2 hours after dosing then decreased in parallel with the maternal blood concentration. The amniotic fluid concentration peaked about 7 hours after administration, then decreased slowly. The absolute transfer ratios to fetus and amniotic fluid were calculated to be about 2.5 and 0.37% respectively.

Pharmacokinetics of Flomoxef in Mucosal Tissue of the Middle Ear and Mastoid Following Intravenous Administration in Humans

The pharmacokinetics of flomoxef in serum and in the mucosal tissue of the middle ear and mastoid were studied in 9 patients undergoing tympanoplasties. All patients received 1 g of flomoxef intravenously. Flomoxef levels in serum and in mucosal tissue were determined by a bioassay method. The peak value of mean concentrations of flomoxef in the mucosal tissue was 30.3 +/- 11.7 micrograms/ml at 10 min after the administrations. Pharmacokinetic analyses showed that the concentration of flomoxef in the mucosal tissue was over 1.56 micrograms/ml (which is the MIC90 for the common pathogens of otitis media) for more than 2 h and decreased parallel with serum concentration with a half-life of about 40 min.