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Safety and pharmacokinetics of intrathecal administration of pemetrexed in rats

Authors
 Jong-Mu Sun  ;  Mi Hyun Nam  ;  Jae Yong Chung  ;  Bohee Im  ;  Soo-Youn Lee  ;  Youn-Lim Suh  ;  Jin Seok Ahn  ;  Keunchil Park  ;  Myung-Ju Ahn 
Citation
 CANCER CHEMOTHERAPY AND PHARMACOLOGY, Vol.68(2) : 531-538, 2011 
Journal Title
 CANCER CHEMOTHERAPY AND PHARMACOLOGY 
ISSN
 0344-5704 
Issue Date
2011
MeSH
Animals ; Antimetabolites, Antineoplastic/administration & dosage* ; Antimetabolites, Antineoplastic/adverse effects* ; Antimetabolites, Antineoplastic/analysis ; Antimetabolites, Antineoplastic/pharmacokinetics ; Catheters, Indwelling ; Chromatography, High Pressure Liquid ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Glutamates/administration & dosage* ; Glutamates/adverse effects* ; Glutamates/analysis ; Glutamates/pharmacokinetics ; Guanine/administration & dosage ; Guanine/adverse effects ; Guanine/analogs & derivatives* ; Guanine/analysis ; Guanine/pharmacokinetics ; Half-Life ; Injections, Spinal ; Male ; Metabolic Clearance Rate ; Neurons/drug effects* ; Neurons/pathology ; Neurotoxicity Syndromes*/blood ; Neurotoxicity Syndromes*/cerebrospinal fluid ; Neurotoxicity Syndromes*/pathology ; No-Observed-Adverse-Effect Level ; Pemetrexed ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Space ; Tandem Mass Spectrometry ; Tissue Distribution ; Toxicity Tests
Keywords
Pemetrexed ; Leptomeningeal carcinomatosis ; Pharmacokinetics ; Toxicity
Abstract
PURPOSE: Leptomeningeal carcinomatosis is a devastating complication of malignant disease. In this study, we evaluated the safety and pharmacokinetics of intrathecally administered pemetrexed in rats. METHODS: Three levels of pemetrexed (0.3, 1, and 3 mg/kg) were administered to 15 rats per level (45 rats in total) twice a week for 2 weeks through specifically designed indwelling subarachnoid catheters. Presence of clinical and pathological neurotoxicity was evaluated. To evaluate the pharmacokinetics of pemetrexed, independent cohorts of 30 rats were treated with 1 mg/kg of pemetrexed and its concentration in cerebrospinal fluid (CSF) and blood was measured using UPLC/MS/MS. RESULTS: There were no cases of clinical or pathologic neurotoxicity after intrathecal administrations of pemetrexed at levels of 0.3 and 1 mg/kg; however, 5 of 15 (33%) rats died after administration of 3 mg/kg pemetrexed. The distribution/elimination of pemetrexed in CSF was best described by a two-compartment model, with initial and terminal half-lives of 0.43 and 1.43 h, respectively. The predicted maximal concentration in CSF was 588 μM, and high levels of pemetrexed appeared to be maintained for a long time. Area under the curve and volume of distribution at steady state were 560 μM h and 1.14 ml, respectively. CONCLUSIONS: The no observed adverse effect level of intrathecal administration of pemetrexed was 1 mg/kg in rats. At this level, therapeutically high and durable pemetrexed concentrations could be achieved. Based on these results, further research on intrathecal pemetrexed in humans or non-human primates should be considered.
Full Text
http://link.springer.com/article/10.1007%2Fs00280-010-1522-7
DOI
10.1007/s00280-010-1522-7
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Chung, Jae Yong(정재용)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/93458
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