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Clinical Pharmacology of Deoxyspergualin in Patients with Advanced Cancer¹

Clinical Pharmacology Laboratory [J. F. M., S-J. L., L. B.], and the Developmental Chemotherapy [C. W. Y.] and Solid Tumor [H. I. S., A. J.] Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, New York 10021, and Departments of Pharmaceutical Chemistry [L. A. S., C. M. R.], and Medicinal Chemistry [D. V. V.], University of Kansas, Lawrence, Kansas 66045

Pharmacokinetic studies were carried out in 25 patients with advanced cancer receiving deoxyspergualin (DSG), a candidate anticancer agent, in a dose-finding Phase I study. The dosage range explored was 80 to 2160 mg/m²/day for 5 days by continuous i.v. infusion. The drug levels in plasma and urine were measured by high-performance liquid chromatography with postcolumn derivatization and fluorescence detection. One drug metabolite was demonstrated in plasma and urine of treated patients. This metabolite was extracted from urine and purified to homogeneity; thereafter, it was examined by high-performance liquid chromatography, nuclear magnetic resonance, and fragmentation mass spectrometry and was demonstrated to be identical to chemically synthesized desaminopropyl-DSG. The mean steady state plasma concentrations of DSG ranged from 0.28 to 11.1 µM at, respectively, the 80- and 2160-mg/m² dosage levels. The plasma concentration at steady state and the area under the plasma concentration versus time curve of DSG were proportional to dose (r = 0.97). Following discontinuance of the infusion, DSG was cleared from the plasma in a biexponential fashion. The mean total body clearance was 364 ± 78 ml/min/m². Desaminopropyl-DSG was formed extensively at all dosage levels; mean steady state plasma levels of this metabolite reached a plateau 2.65 µM at a dose of 720 mg/m²/day and did not rise with further dose increments. The urinary content of DSG was examined in 20 patients over the dosage range from 160 to 960 mg/m²/day; in this group less than 10% of the administered dose was excreted as DSG. In four patients at the 720- and 960-mg/m²/day dosage levels, the total DSG plus metabolite excretion ranged from 7 to 18% of the administered dose, with comparable quantities occurring as the parent drug and desaminopropyl-DSG.

¹ Supported in part by USPHS Grants CA 05826 and CA 08748 and by Contract NO1-CM-57732 from the National Cancer Institute (to Memorial Sloan-Kettering Cancer Center); a National Cancer Institute Training Grant, CA 09242 (to K. U.); and a fellowship grant from the J. M. Foundation (S. J. L.). Presented in part at the 79th Annual Meeting of the American Association for Cancer Research, May 25–28, 1988, New Orleans, LA.

² To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

³ Present address: Chung-Ang University Hospital, Yongsan-Ku, Seoul, 140, Korea.

Received 7/31/90. Accepted 4/ 9/91.

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