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Comparative Pharmacokinetics of 1-(2-Chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea in Rats and Patients and Extrapolation to Clinical Trials¹

Brain Tumor Research Center, Department of Neurological Surgery, School of Medicine [V. A. L., R. J. W., J. L.], and the Department of Pharmaceutical Chemistry, School of Pharmacy [V. A. L., R. J. W.], University of California, San Francisco, California 94143

The plasma pharmacokinetics of 1-(2-chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea (PCNU) were determined in ambulatory rats and in patients receiving PCNU chemotherapy in Phase 1 and II studies. After derivativization to the methyl carbamate, both rat and human PCNU plasma levels were measured by gas chromatography-mass spectrometry. Comparison of the tolerated dose levels and pharmacokinetics of PCNU to the values determined for 1,3-bis(2-chloroethyl)-1-nitrosourea in humans indicated that PCNU has a lower plasma drug area under the curve at equitoxic doses. We conclude that PCNU may show less clinical efficacy than 1,3-bis(2-chloroethyl)-1-nitrosourea in the treatment of solid tumors.

¹ Supported by NIH Grant CA-13525.

² Recipient of American Cancer Society Faculty Research Award FRA-155. To whom requests for reprints should be addressed, at Brain Tumor Research Center, 783 HSW, School of Medicine, University of California, San Francisco, Calif. 94143.

³ Present address: Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Pharmacy Building, Purdue University, West Lafayette, Ind. 47907.

Received 12/ 1/80. Accepted 6/11/81.