TY - JOUR
T1 - Lack of ranitidine effects on cyclophosphamide bon marrow toxicity or metabolism
T2 - A placebo-controlled clinical trial
AU - Alberts, David S.
AU - Mason-liddil, Nancy
AU - Plezia, Patricia M.
AU - Roe, Denise J.
AU - Dorr, Robert T.
AU - Struck, Robert F.
AU - Phillips, J. Gregory
N1 - Funding Information:
Received December 17, 1990; revised June 27, 1991; accepted September 10, 1991. Supported by Public Health Service grants CA-17094, CA-23074, and CA-46951 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; and by a grant from Glaxo Pharmaceutical Co., Research Triangle Park, N.C. D. S. Alberts, R. T. Dorr, Section of Hematology and Oncology, Department of Medicine and Department of Pharmacology, Arizona Cancer Center, College of Pharmacy, University of Arizona, Tucson, Ariz. N. Mason-Liddil, Arizona Cancer Center, University of Arizona. P. M. Plezia, Section of Hematology and Oncology, Department of Medicine, and Arizona Cancer Center, College of Medicine and the Department of Pharmacy Practice, University of Arizona. D. J. Roe, Department of Family and Community Medicine, Arizona Cancer Center, University of Arizona. R. F. Struck, J G. Phillips, Southern Research Institute, Birmingham, Ala. 'Correspondence to: David S. Alberts, M.D., Arizona Cancer Center, 1515 N. Campbell Ave., Tucson, AZ 85724.
PY - 1991/4/4
Y1 - 1991/4/4
N2 - We previously reported that cimetidine but not ranitidine significantly enhances cyclophosphamide-induced bone marrow toxic effects and the appearance of cyclophosphamide alkylating species in a murine leukemia mouse model, and we advised caution in the use of cimetidine with microsomally metabolized anticancer drugs. Both drugs have been used for the treatment of gastric complications of chemotherapy. Using a randomized, double-blind, crossover study design, we have now evaluated the potential interaction of ranitidine with cyclophosphamide in seven cancer patients, who received two courses of cyclophosphamide, one with ranitidine and one with placebo. Four patients received ranitidine in the first course, and three received placebo. Ranitidine or placebo was started 3 days before a single dose of cyclophosphamide and given for 17 consecutive days. Ranitidine or placebo was given orally (300 mg/d), and cyclophosphamide (600 mg/m2) was given intravenously with [3H]cyclophospha-mide (1000 μCi). Cyclophosphamide treatment was repeated at 4 weeks plus or minus 4 days. Blood samples were collected at intervals from 5 minutes to 24 hours after cyclophosphamide treatment and analyzed by thin-layer chromatography and radioassay for the drug and its metabolites. On days 0, 7, 14, and 21 after cyclophosphamide administration, complete blood cell counts, white blood cell differential counts, platelet counts, and SMA-17 were determined. The differences in mean nadir white blood cell counts, granulocyte counts, hemoglobin levels, and hematocrit values during ranitidine versus placebo treatment were not statistically significant In a statistical but not a clinical sense, mean nadir platelet counts were significantly lower with ranitidine. There was a statistically significant increase in area under the curve for drug concentration in plasma x time (AUC) with ranitidine as well as a statistically significant decrease in the total-body clearance rate of the cyclophosphamide molecule. However, the effect on AUC for the major oncolytic metabolites 4-hydroxycyclophospha-mide and phosphoramide mustard was not statistically significant. The lack of toxicologic or metabolic interaction between ranitidine and cyclophosphamide suggests that ranitidine can be used safely with cyclophosphamide. [J Natl Cancer Inst 83:1739-1743, 1991]
AB - We previously reported that cimetidine but not ranitidine significantly enhances cyclophosphamide-induced bone marrow toxic effects and the appearance of cyclophosphamide alkylating species in a murine leukemia mouse model, and we advised caution in the use of cimetidine with microsomally metabolized anticancer drugs. Both drugs have been used for the treatment of gastric complications of chemotherapy. Using a randomized, double-blind, crossover study design, we have now evaluated the potential interaction of ranitidine with cyclophosphamide in seven cancer patients, who received two courses of cyclophosphamide, one with ranitidine and one with placebo. Four patients received ranitidine in the first course, and three received placebo. Ranitidine or placebo was started 3 days before a single dose of cyclophosphamide and given for 17 consecutive days. Ranitidine or placebo was given orally (300 mg/d), and cyclophosphamide (600 mg/m2) was given intravenously with [3H]cyclophospha-mide (1000 μCi). Cyclophosphamide treatment was repeated at 4 weeks plus or minus 4 days. Blood samples were collected at intervals from 5 minutes to 24 hours after cyclophosphamide treatment and analyzed by thin-layer chromatography and radioassay for the drug and its metabolites. On days 0, 7, 14, and 21 after cyclophosphamide administration, complete blood cell counts, white blood cell differential counts, platelet counts, and SMA-17 were determined. The differences in mean nadir white blood cell counts, granulocyte counts, hemoglobin levels, and hematocrit values during ranitidine versus placebo treatment were not statistically significant In a statistical but not a clinical sense, mean nadir platelet counts were significantly lower with ranitidine. There was a statistically significant increase in area under the curve for drug concentration in plasma x time (AUC) with ranitidine as well as a statistically significant decrease in the total-body clearance rate of the cyclophosphamide molecule. However, the effect on AUC for the major oncolytic metabolites 4-hydroxycyclophospha-mide and phosphoramide mustard was not statistically significant. The lack of toxicologic or metabolic interaction between ranitidine and cyclophosphamide suggests that ranitidine can be used safely with cyclophosphamide. [J Natl Cancer Inst 83:1739-1743, 1991]
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U2 - 10.1093/jnci/83.23.1739
DO - 10.1093/jnci/83.23.1739
M3 - Article
C2 - 1770553
AN - SCOPUS:0025932465
SN - 0027-8874
VL - 83
SP - 1739
EP - 1743
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 23
ER -