Clinical pharmacology of trimetrexate.
Clinical pharmacology of trimetrexate.
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曲美曲沙的临床药理学。
DOI：
10.1038/clpt.1987.160
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发表时间：
1987
影响因子：
6.7
通讯作者：
Krakoff,IH
中科院分区：
文献类型：
--
作者：
Ho,DH;Covington,WP;Legha,SS;Newman,RA;Krakoff,IH
在I期试验期间，在11名患者中测定了曲美蝶呤的临床药代动力学。血浆药物消失曲线为三相，t1/2α为8 ± 5分钟，t1/2β为102 ± 48分钟，t1/2γ为15.2 ± 5.7小时。AUC为373 ± 336（μg/ml）hr（标准化为200 mg/m2剂量），面积法分布容积（V）为25.2 ± 16.1 L/m2，总清除率（CL）为14 ± 8 ml/min/m2，肾清除率（CL）为8 ± 6 ml/min/m2。4例接受190 - 200 mg/m2的患者未发生严重毒性。然而，接受120 - 210 mg/m2剂量的3例患者发生重度骨髓抑制、皮疹和口腔炎。后一组具有显著更长的终末半衰期、更大的AUC、更小的Vareas以及更低的CL和Cmax率。其中1例患者因肥胖而接受了异常大量的曲美蝶呤（470 mg）。其余两名患者有肾脏问题。1例患者由于肾功能受损，尽管接受了降低剂量（120 mg/m2），但仍发生了毒性。另一名患者肾功能正常，有腹水，并因肾癌接受了单侧肾切除术。这些数据表明，长期暴露于高水平的三甲蝶呤可能会导致毒性增加。对于肾功能不全的患者，可能需要考虑调整剂量。临床药理学和治疗学（1987）42，351 -356; doi：10.1038/clpt.1987.160
The clinical pharmacokinetics of trimetrexate were determined in 11 patients during the phase I trial. The plasma drug disappearance curve was triphasic, with a t1/2αof 8 ± 5 minutes, t1/2βof 102 ± 48 minutes, and t1/2γof 15.2 ± 5.7 hours. The AUC was 373 ± 336 (μg/ml) hr (normalized to a dose of 200 mg/m2), volume of distribution by the area method (V) was 25.2 ± 16.1 L/m2, total clearance (CL) was 14 ± 8 ml/min/m2, and renal clearance (CLR) was 8 ± 6 ml/min/m2. Four patients who received 190 to 200 mg/m2did not develop severe toxicity. However, three patients who received 120 to 210 mg/m2developed severe myelosuppression, skin rash, and stomatitis. This latter group had significantly longer terminal half‐lives, greater AUCs, smaller Vareas, and lower rates of CL and CLR. One of these patients received an unusually large total amount of trimetrexate (470 mg) because of his obesity. The remaining two patients had renal problems. One developed toxicity despite having received a reduced dose (120 mg/m2) because of impaired renal function. The other patient, with normal renal function, had ascites and had undergone a unilateral nephrectomy for renal carcinoma. These data suggest that prolonged exposure to high trimetrexate levels may lead to increased toxicity. Dosage adjustment may have to be considered for patients who have renal dysfunction.Clinical Pharmacology and Therapeutics(1987)42,351–356; doi:10.1038/clpt.1987.160