Human Pharmacokinetics, Excretion, and Metabolism of the Anthracycline Antibiotic Menogaril (7-OMEN, NSC 269148) and Their Correlation with Clinical Toxicities

Authors

Merrill J. Egorin
David A. Van Echo
Margaret Y. Whitacre
Alan Forrest
Lawrence M. Sigman
Kathrin L. Engisch, Wright State University - Main CampusFollow
Joseph Aisner

Document Type

Article

Publication Date

3-1986

Abstract

In a Phase I study, menogaril (7-OMEN) was administered daily for 5 days/course, every 21–28 days. Dosages of 3.5, 7, 11.5, 17, and 31.5 mg/m² were infused over 1 h, and dosages of 42, 50, and 56 mg/m² were infused over 2 h. Pharmacokinetics was studied at all dosages. Plasma and urine samples were collected from 24 patients, and bile samples were also collected from 2 patients. 7-OMEN and metabolites were measured by high performance liquid chromatography. 7-OMEN was the major plasma fluorescent species at all times, with only trace amounts of N-demethyl menogaril observed. 7-OMEN disappeared from plasma biexponentially with t_½ α 0.19 ± 0.04 (mean ± SE) h and t_½ β 13.22 ± 1.54 h. Plasma pharmacokinetics of 7-OMEN was linear from 3.5–56 mg/m²; area under the curve increased proportionally with dosage. Total body clearance of 7-OMEN was 28.18 ± 3.33 liter/m²/h, V_c was 224 ± 30.8 liter/m², and V_ss was 370 ± 25.7 liter/m². Plasma pharmacokinetics of 7-OMEN studied on multiple days of a given course were similar. Urinary excretion of 7-OMEN and fluorescent metabolites accounted for 5.4 ± 0.4% of the daily dose. Parent compound still represented ≥80% of urinary drug fluorescence after 24 h. N-demethyl menogaril was the only other fluorescent drug species detected in urine. In two patients with biliary tract drains, biliary excretion of drug fluorescence accounted for 2.2–4.2% of the daily dose. Only 7-OMEN and N-demethyl menogaril were detected in bile by high performance liquid chromatography and thin layer chromatography. 7-OMEN was the major fluorescent biliary species, but, by 24 h, N-demethyl menogaril accounted for approximately 40% of biliary drug fluorescence. When considered in light of each patient's observed toxicities, excellent relationships were observed between the plasma area under the curve of 7-OMEN and the percentage of decreases in WBC and absolute neutrophil count. These latter findings should be useful in developing more precise and intelligent dosing schemes for 7-OMEN.

Comments

© 1986 American Association for Cancer Research.

Repository Citation

Egorin, M. J., Van Echo, D. A., Whitacre, M. Y., Forrest, A., Sigman, L. M., Engisch, K. L., & Aisner, J. (1986). Human Pharmacokinetics, Excretion, and Metabolism of the Anthracycline Antibiotic Menogaril (7-OMEN, NSC 269148) and Their Correlation with Clinical Toxicities. Cancer Research, 46 (3), 1513-1520.
https://corescholar.libraries.wright.edu/ncbp/619