Bremnes R M, Smeland E, Willassen N P, Wist E, Aarbakke J
Department of Pharmacology, University of Tromsø, Norway.
Cancer Chemother Pharmacol. 1991;28(5):377-83. doi: 10.1007/BF00685693.
The inhibition of methotrexate (MTX) biotransformation to 7-hydroxymethotrexate (7-OH-MTX) by 4'-(9-acridinylamino)-methanesulfon-m-anisidide (mAMSA) was studied in bile-drained rats in vivo and in incubates of isolated rat hepatocytes and rat-liver homogenate in vitro. In vivo, i.v. administration of 10 mg/kg mAMSA prior to [3H]-MTX infusion (50 mg/kg) led to a significant alteration in 7-OH-MTX kinetics. 7-OH-MTX peak concentrations and AUC in bile and serum were reduced by 75% and the recovery of MTX as 7-OH-MTX in bile and urine decreased by 70%, whereas MTX pharmacokinetics remained unaltered. In suspensions of isolated hepatocytes, 10 microM mAMSA led to a 54% decrease in 7-OH-MTX formation. However, the hepatocellular influx and efflux of MTX was not perturbed by mAMSA. Preincubation of rat-liver homogenates with 1.25-10 microM mAMSA reduced the formation of 7-OH-MTX by up to 73%. mAMSA appeared to inhibit MTX hydroxylation competitively, exhibiting a Ki of 3 microM. Due to its inhibition of the MTX-oxidizing system, mAMSA may be beneficial in combination chemotherapy with MTX by reducing 7-OH-MTX-associated toxicity and, possibly, enhancing the cytotoxic effects of MTX.
在体内胆汁引流大鼠以及体外分离的大鼠肝细胞和大鼠肝脏匀浆孵育体系中，研究了4'-（9-吖啶基氨基）-甲磺酰间茴香胺（mAMSA）对甲氨蝶呤（MTX）向7-羟基甲氨蝶呤（7-OH-MTX）生物转化的抑制作用。在体内，静脉注射[3H]-MTX（50 mg/kg）前静脉注射10 mg/kg mAMSA会导致7-OH-MTX动力学发生显著改变。胆汁和血清中7-OH-MTX的峰值浓度和AUC降低了75%，胆汁和尿液中以7-OH-MTX形式存在的MTX回收率降低了70%，而MTX的药代动力学保持不变。在分离的肝细胞悬液中，10 μM mAMSA导致7-OH-MTX生成减少54%。然而，MTX的肝细胞内流和外流不受mAMSA干扰。用1.25 - 10 μM mAMSA预孵育大鼠肝脏匀浆可使7-OH-MTX的生成减少多达73%。mAMSA似乎竞争性抑制MTX羟基化，其Ki为3 μM。由于mAMSA对MTX氧化系统的抑制作用，它在与MTX联合化疗中可能有益，可降低与7-OH-MTX相关的毒性，并可能增强MTX的细胞毒性作用。
