BLOOD LEVEL OF CYCLOPHOSPHAMIDE IN PERORAL ADMINISTRATION

Abstract

Blood level of cyclophosphamide (Endoxan, Ex) after peroral administration has not yet been fully elucidated, in spite of its wide clinical application as a masked form of antitumor agents. The present study was designed to determine the reasonable peroral dose of Ex by measuring blood and urinary level and comparing them with the values in the intravenous route.
The blood levels of total Ex (i. e. indirectly reactive substances for NBP reagent) and its metabolites were measured in consecutive 2 nd, 6 th and 24 th hours according to FRIEDMAN-MORITA'S method after 200 mg Ex administration in the form of tablet containing 50 mg (T-Group) or granule (G-Group) containing 50 mg a gram. Difference of the form of drug, i. e. between tablets and granules, and of the administration routes, i. e. between peroral and intravenous route were compared. Thirty-six patients cinluding malignant lymphoma, carcinoma of skin, breast and thyroid without any gastrointestinal disorders, were materials for the present study and their body weights ranged 50-56 kg.
As previously reported on 43 patients of malignant tumor, the mean blood levels after intravenous administration of 500 mg Ex were, as the total substances, 7. 4 μg/ml in 1st, 6. 5 μg/ml in 2 nd, 6.7 pg/ml in 3 rd and 3. 8μg/ml in 24 th hour, respectively, and as metabolites form, 3. 2 jug/ml in 1st, 2. 8 μg/ml in 2 nd, 2. 4μg/ml in 3 rd and 3. 0 dug/ml in 24 th hour, respectively.
Maximal activation rates (directly reactive substance over indirectly reactive substance) in 24 hours after intravenous administration showed 79%. Mean maximal blood level was obtained after 6 hours in single peroral administration of 200 mg Ex. The levels in G-Group showed 7. 8 μg/ml in total substances and 5. 4 μg/ml in metabolites, respectively, and those in T-Group were 5. 8 μg/ml in total substances and 4. 6μg/ml in metabolites, showing higher value in G-Group. The blood levels of 24 hours after peroral administration were somewhat higher than those after 6 hours in T-Group, but the former was slightly lower than the latter in G-Group. Since the difference between the values in 6 th and 24 th hour was minimal, it might be suggested that the blood level was not so much affected by the dose given perorally.
The blood levels after peroral administration of 500 mg Ex, were similar to those of 200 mg, showing 6.2μg/ml in total substances and 3. 2μg/ml in metabolites in T-Group and 11. 6 fig/ml in the former and 6. 1μg/ml in the latter in G-Group, respectively. It was noticed, therefore, that there might be no differences in metabolites between the administration route and dosis.
Urinary excretion of Ex after 200 mg peroral administration were minimal within initial 2 hours, but 6-20% and 25-50% of Ex were excreted for subsequent 4 and following 18 hours and its activation rates was approximately 50%.
The blood levels of consecutive 1st, 7 th, 14 th and 21 st days after peroral administration of 200 mg Ex per day, were almost unchanged both in T-and G-Group, revealing the same level as in single administration of 200 mg a day. Even in the peroral administration of consecutively decreasing dose, such as 500 mg on 1 st, 300 mg on 2 nd, 200 mg on 3 rd and 100 mg on 4 th day, the blood level of Ex was not altered and this was lowered and disappeared by 3 rd day after the administration was discontinued.
From the results obtained, peroral administration of 200 to 300 mg Ex per day was recommended as the necessary and sufficient maintenance dose.