Park J M, Ahn B N, Yoon E J, Lee M G, Shim C K, Kim C K
College of Pharmacy, Seoul National University, Korea.
Biopharm Drug Dispos. 1994 Jul;15(5):391-407. doi: 10.1002/bdd.2510150506.
The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (i.v.) injection of free MTX (treatment I), MTX-loaded proliposomes (treatment II), and empty proliposomes mixed manually with free MTX (treatment III), 8 mg kg-1, to rats using an HPLC assay. After i.v. infusion in 1 min, the plasma concentration of MTX (Cp), the area under the plasma concentration-time curve (AUC, 639 versus 913 micrograms min mL-1), the terminal half-life (t1/2, 48.8 versus 397 min), the mean residence time (MRT, 8.40 versus 325 min), and the apparent volume of distribution at steady state (Vss, 98.1 versus 2800 mL kg-1) were significantly higher; however, the total body clearance (CL, 12.5 versus 8.76 mL min-1 kg-1), renal clearance (CLR, 4.49 versus 2.78 mL min-1 kg-1), non-renal clearance (CLNR, 7.50 versus 5.99 mL min-1 kg-1), and the amount of MTX excreted in urine (Xu, 808 versus 685 micrograms, p < 0.0948) were significantly lower from treatment II than from treatment I. This could be due to the fact that some of the MTX-loaded liposomes (formed immediately after hydration of MTX-loaded proliposomes) are entrapped in tissues and the rest are present in the plasma (higher MRT and Vss from treatment II), and MTX is slowly released from MTX-loaded liposomes (higher t1/2 from treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX loaded in liposomes (higher Cp and AUC, slower CL from treatment II). After i.v. infusion in 1 min, some pharmacokinetic parameters, such as t1/2, MRT, and Vss, were significantly different between treatments I and III; however, the differences seemed to be smaller than those between treatments I and II. After 30 min from i.v. infusion, the tissue to plasma (T/P) ratios of MTX in kidney and stomach from treatment II were significantly lower than those from treatment I. This suggested that the i.v. administration of MTX-loaded proliposomes might have fewer side effects in the organs than that of free MTX. The mean amount of MTX loaded in MTX-loaded proliposomes was 2.54 mg/g proliposomes and the MTX was released slowly from hydrated MTX-loaded proliposomes when incubated with phosphate-buffered saline (PBS), rat plasma, or rat liver homogenate.
采用高效液相色谱法（HPLC）测定，给大鼠静脉注射8mg/kg游离甲氨蝶呤（治疗I）、载甲氨蝶呤前体脂质体（治疗II）以及手动混合游离甲氨蝶呤的空白前体脂质体（治疗III）后，研究了甲氨蝶呤（MTX）的药代动力学和组织分布。静脉输注1分钟后，治疗II组MTX的血浆浓度（Cp）、血浆浓度-时间曲线下面积（AUC，分别为639和913μg·min/mL）、末端半衰期（t1/2，分别为48.8和397分钟）、平均驻留时间（MRT，分别为8.40和325分钟）以及稳态表观分布容积（Vss，分别为98.1和2800mL/kg）显著更高；然而，治疗II组的总体清除率（CL，分别为12.5和8.76mL·min-1/kg）、肾清除率（CLR，分别为4.49和2.78mL·min-1/kg）、非肾清除率（CLNR，分别为7.50和5.99mL·min-1/kg）以及尿中甲氨蝶呤排泄量（Xu，分别为808和685μg，p<0.0948）显著低于治疗I组。这可能是因为一些载甲氨蝶呤脂质体（载甲氨蝶呤前体脂质体水化后立即形成）被困在组织中，其余的存在于血浆中（治疗II组MRT和Vss更高），并且甲氨蝶呤从载甲氨蝶呤脂质体中缓慢释放（治疗II组t1/2更高）。在本HPLC测定中，MTX的浓度代表游离MTX和脂质体中载有的MTX的总和（治疗II组Cp和AUC更高，CL更慢）。静脉输注1分钟后，治疗I和III组之间的一些药代动力学参数，如t1/2、MRT和Vss，存在显著差异；然而，这些差异似乎小于治疗I和II组之间的差异。静脉输注30分钟后，治疗II组肾脏和胃中甲氨蝶呤的组织/血浆（T/P）比值显著低于治疗I组。这表明静脉注射载甲氨蝶呤前体脂质体对器官的副作用可能比游离甲氨蝶呤少。载甲氨蝶呤前体脂质体中载有的MTX平均量为2.54mg/g前体脂质体，当与磷酸盐缓冲盐水（PBS）、大鼠血浆或大鼠肝匀浆孵育时，MTX从水化的载甲氨蝶呤前体脂质体中缓慢释放。
