Ishizawa T, Hayashi M, Awazu S
Pharmaceutical Research Laboratories, Meiji Seika Kaisha, Ltd., Kanagawa, Japan.
J Pharmacobiodyn. 1991 Feb;14(2):82-6. doi: 10.1248/bpb1978.14.82.
Intestinal absorption mechanism of fosfomycin (FOM), a water-soluble and small molecular antibiotic, at the clinical dose level was examined by both in situ single-pass perfusion technique of rat small intestine and oral administration in rat in vivo. Analyzing the luminal concentration-dependence of FOM absorption rates in situ by the equation composed of two terms of carrier transport of Michaelis-Menten type and simple-diffusion, apparent Michaelis constant (Kt), maximal transport velocity (Jmax), and first-order diffusive absorption clearance (Kd) were 1.13 mM, 2.54 nmol/min/cm length, and 0.551 microliters/min/cm length, respectively. At the low FOM concentration in the lumen (0.1 mM), its absorption was reduced to about 60% of the control by inorganic phosphate ion at 1.0 mM in the same manner as the uptake in brush border membrane vesicles of rat small intestine (BBMVs) in vitro. Both the glycol form of FOM at 10 mM, the hydrolyzed metabolite of FOM in the stomach juice, and FOM itself at 10 mM reduced FOM absorption by about 50%, indicating the metabolite to be transported by the same carriers as those of FOM. At the higher FOM concentration (5 mM), its absorption was not reduced by any inhibitor described above. No inhibitory effect of 50 mM phosphate ion on FOM absorption following the oral dosing of 20 mg/kg FOM was found. It was concluded that FOM absorption at the clinical dose (10-20 mg/kg) is barely inhibited by the carrier-mediated system via phosphate transport system observed in the in vitro BBMVs.
采用大鼠小肠原位单通道灌注技术和大鼠体内口服给药的方法，研究了临床剂量水平下水溶性小分子抗生素磷霉素（FOM）的肠道吸收机制。通过由米氏类型的载体转运和简单扩散的两项组成的方程原位分析FOM吸收速率的管腔浓度依赖性，表观米氏常数（Kt）、最大转运速度（Jmax）和一级扩散吸收清除率（Kd）分别为1.13 mM、2.54 nmol/min/cm长度和0.551微升/min/cm长度。在管腔中低浓度的FOM（0.1 mM）时，1.0 mM的无机磷酸根离子使其吸收降低至对照的约60%，与体外大鼠小肠刷状缘膜囊泡（BBMVs）中的摄取方式相同。10 mM的FOM糖醛酸形式（胃液中FOM的水解代谢物）和10 mM的FOM本身均使FOM吸收降低约50%，表明该代谢物与FOM通过相同的载体转运。在较高浓度的FOM（5 mM）时，其吸收不受上述任何抑制剂的影响。口服20 mg/kg FOM后，未发现50 mM磷酸根离子对FOM吸收有抑制作用。得出结论：在临床剂量（10 - 20 mg/kg）下，FOM的吸收几乎不受体外BBMVs中观察到的通过磷酸盐转运系统的载体介导系统的抑制。
