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Pharmacological Disposition of 1-(2-Chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea in Mice¹

Department of Medicine, Division of Medical Oncology and Department of Pharmacology [P. S. S., P. V. W.], and Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, D. C. 20007

1-(2-Chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU; NSC 95466) is a lipid-soluble nitrosourea that is presently in clinical trial. We have studied the pharmacological disposition of [ethyl-¹⁴C]PCNU in mice using an i.v. drug dose of 20 mg/kg/animal. Disappearance of total radioactivity from plasma was biphasic with mean half-lives of the two exponential phases of 21.7 min and 27.4 hr, respectively. The plasma half-life of intact drug was 29 min, and levels of intact drug, as measured by thinlayer chromatography, fell below detectable levels by 4 hr. The area under the plasma concentration-time curve for intact drug was 32.72 nmol·hr/ml. Computer analysis of the data for total radioactivity (PCNU equivalents), based upon an open two-compartment model, yielded values of the pharmacokinetic parameters K₁₂, K₂₁, and K₁₀ of 1.49 hr^-1, 0.25 hr^-1, and 0.19 hr^-1, respectively. The highest peak organ level of drug was 168.9 nmol of PCNU equivalents per g tissue in the liver 1 hr after drug administration. Maximum levels in kidney, lungs, heart, and spleen were observed at 5 min, with values of 119.5, 115.4, 80.3, and 66.7 nmol of PCNU equivalents per g of tissue, respectively. A high peak drug level in brain (50.6 nmol/g) agreed with the prediction that PCNU can cross the blood-brain barrier. The levels of intact drug relative to total radioactivity at 30 min were 60% in brain, 55% in heart, and 48% in spleen. The concurrent value in liver was 7% of the total radioactivity, suggesting that metabolism or decomposition of PCNU occurs in this organ. The principal excretory route of [ethyl-¹⁴C]PCNU was urinary, with a cumulative excretion of 62% in the first 24 hr.

¹ This investigation was supported by National Cancer Institute Contract N01-CM-97208, Division of Cancer Treatment, Investigational Drug Branch.

² To whom requests for reprints should be addressed, at Division of Medical Oncology, Georgetown University Hospital, 3800 Reservoir Road N. W., Washington, D. C. 20007.

Received 1/13/81. Accepted 10/ 4/83.