Welage L S, Hejmanowski L G, Wilton J H, Walawander C, Rigan D, Williams J S, Schentag J J
State University of New York, Buffalo School of Pharmacy.
Antimicrob Agents Chemother. 1989 Jun;33(6):857-61. doi: 10.1128/AAC.33.6.857.
The N-methylthiotetrazole side chain (NMTT) that is present on several cephalosporins has been implicated in the development of antibiotic-associated hypoprothrombinemia. A randomized three-way crossover trial was conducted to compare the release of the NMTT side chain from three NMTT-containing antibiotics. Single 2-g doses of moxalactam, cefoperazone, and cefotetan were given, followed by serial blood and urine sampling. The concentrations of the parent compound and the NMTT side chain in plasma, urine, and the reconstituted antibiotic solution were determined by high-pressure liquid chromatography. Peak NMTT concentrations ranged from 0.42 to 16.50 micrograms/ml and were significantly higher after moxalactam administration than after cefoperazone or cefotetan administration (P less than 0.01). The NMTT trough concentrations (12.5 h) ranged from nondetectable to 2.47 micrograms/ml and tended to be greater following cefoperazone administration. The amounts of NMTT administered (e.g., the amount in the reconstituted antibiotic solution) were 25.8 +/- 1.4, 15.2 +/- 0.9, and 22.1 +/- 3.0 mg following moxalactam, cefoperazone, and cefotetan administration, respectively (P less than 0.01). In contrast, urinary recoveries of NMTT were 57.4 +/- 26.2, 73.6 +/- 44.3, and 29.7 +/- 22.9 mg following moxalactam, cefoperazone, and cefotetan, respectively. The amount of NMTT formed in vivo and excreted unchanged, as assessed by subtracting in vitro NMTT formation from NMTT urinary recovery, was significantly higher after cefoperazone than after moxalactam or cefotetan administration (P less than 0.05). The discrepancy between in vitro NMTT production (moxalactam > cefotetan > cefoperazone) and the amount of NMTT formed in vivo and excreted unchanged (cefoperazone > moxalactam > cefotetan) demonstrated that the in vivo production of NMTT is dependent on the disposition of the parent cephalosporin.
几种头孢菌素上存在的N-甲基硫代四唑侧链（NMTT）与抗生素相关性低凝血酶原血症的发生有关。进行了一项随机三向交叉试验，以比较三种含NMTT抗生素中NMTT侧链的释放情况。分别给予单剂量2克的拉氧头孢、头孢哌酮和头孢替坦，随后进行系列血液和尿液采样。通过高压液相色谱法测定血浆、尿液和复溶抗生素溶液中母体化合物和NMTT侧链的浓度。NMTT峰值浓度范围为0.42至16.50微克/毫升，拉氧头孢给药后显著高于头孢哌酮或头孢替坦给药后（P<0.01）。NMTT谷浓度（12.5小时）范围为不可检测至2.47微克/毫升，头孢哌酮给药后往往更高。拉氧头孢、头孢哌酮和头孢替坦给药后，给予的NMTT量（例如复溶抗生素溶液中的量）分别为25.8±1.4、15.2±0.9和22.1±3.0毫克（P<0.01）。相比之下，拉氧头孢、头孢哌酮和头孢替坦给药后，NMTT的尿回收率分别为57.4±26.2、73.6±44.3和29.7±22.9毫克。通过从NMTT尿回收率中减去体外NMTT形成量来评估，头孢哌酮给药后体内形成并原样排泄的NMTT量显著高于拉氧头孢或头孢替坦给药后（P<0.05）。体外NMTT产生量（拉氧头孢>头孢替坦>头孢哌酮）与体内形成并原样排泄的NMTT量（头孢哌酮>拉氧头孢>头孢替坦）之间的差异表明，NMTT的体内产生取决于母体头孢菌素的处置。
