Human pharmacokinetics and toxicity of high-dose metronidazole administered orally and intravenously

Journal Article · Sat Jan 01 04:00:00 EST 1983 · Surgery; (United States)

OSTI ID:6189337

Urtasun, R C; Rabin, H R; Partington, J

This study is part of a clinical program to assess the use of nitroimidazoles as radiosensitizers of hypoxic tumor cells. A total of 37 patients with malignant tumors have been entered into the study to receive oral high-dose metronidazole in conjunction with radiation. Twenty-eight patients with malignant brain tumors received 6 gm/m2 three times a week for 3 weeks (a mean total dose of 5.3 gm/m2). Maximum mean plasma drug concentration of 1 mM was obtained at 4 hours after drug ingestion with a mean half-life of 13 hours. Tissue and cerebrospinal fluid levels of 80% to 90% of the plasma levels were obtained at 4 to 6 hours. A linear relationship between increased drug dose and increased plasma concentration was observed at doses of 2.5 gm/m2 up to 6 gm/m2. Acute gastrointestinal and central nervous system toxicity was the dose-limiting factor (50% and 25%, respectively, at total doses of 5.3 gm/m2). Pharmacokinetic studies of intravenous metronidazole were performed in eight consenting patients. Single doses of 0.5, 1, 1.5, and 2 gm were administered intravenously by zero-order infusion pump. Seven of the eight patients received a second identical dose orally 1 week later and the results were compared. Open two-compartment kinetic characteristics of metronidazole were computed from simultaneous plasma infusion and urine excretion rate equations, by use of a nonlinear least-squares regression analysis program (NONLIN). The mean (+/- SD) for alpha half-life was 1.2 +/- 1.3 hours, and that for the beta half-life was 9.8 +/- 5.9 hours. The absolute oral bioavailability was estimated to approximate 100%.

• Research Organization: Division of Radiation Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alta
• OSTI ID: 6189337
• Journal Information: Surgery; (United States), Journal Name: Surgery; (United States) Vol. 93:2; ISSN SURGA
• Country of Publication: United States
• Language: English

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62 RADIOLOGY AND NUCLEAR MEDICINE
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALCOHOLS
ANTINEOPLASTIC DRUGS
AZOLES
BIOCHEMICAL REACTION KINETICS
BODY
BRAIN
CENTRAL NERVOUS SYSTEM
COMPARATIVE EVALUATIONS
DISEASES
DOSES
DRUGS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
IMIDAZOLES
KINETICS
MEDICINE
METABOLISM
METRONIDAZOLE
NEOPLASMS
NERVOUS SYSTEM
NITRO COMPOUNDS
NORTH AMERICA
NUCLEAR MEDICINE
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PATIENTS
PHYSIOLOGY
QUANTITY RATIO
RADIATION DOSES
RADIOLOGY
RADIOSENSITIVITY EFFECTS
RADIOSENSITIZERS
RADIOTHERAPY
REACTION KINETICS
THERAPY
TOXICITY
USA