Lack of ranitidine effects on cyclophosphamide bone marrow toxicity or metabolism

A placebo-controlled clinical trial

David S Alberts, Nancy Mason-Liddil, Patricia M. Plezia, Denise Roe, Robert T Dorr, Robert F. Struck, J. Gregory Phillips

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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]cyclophosphamide (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 × 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-hydroxycyclophosphamide 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.

Original languageEnglish (US)
Pages (from-to)1739-1743
Number of pages5
JournalJournal of the National Cancer Institute
Volume83
Issue number23
StatePublished - Dec 4 1991

Fingerprint

Ranitidine
Controlled Clinical Trials
Toxicity
Bone
Metabolism
Clinical Trials
Cyclophosphamide
Count
Blood
Bone Marrow
Placebos
Cells
Drugs
Metabolites
Platelets
Thin layer chromatography
Chemotherapy
Hemoglobin
Cell
Crossover Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging

Cite this

Lack of ranitidine effects on cyclophosphamide bone marrow toxicity or metabolism : A placebo-controlled clinical trial. / Alberts, David S; Mason-Liddil, Nancy; Plezia, Patricia M.; Roe, Denise; Dorr, Robert T; Struck, Robert F.; Phillips, J. Gregory.

In: Journal of the National Cancer Institute, Vol. 83, No. 23, 04.12.1991, p. 1739-1743.

Research output: Contribution to journalArticle

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abstract = "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]cyclophosphamide (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 × 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-hydroxycyclophosphamide 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.",
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