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Penetration of N-(Phosphonacetyl)-L-aspartate into Human Central Nervous System and Intracerebral Tumor¹

Departments of Developmental Therapeutics [D. J. S., J. F., R. S. B., G. P. B., M. V., M. A. B., T. L. L.], Surgery [M. L.], Biochemistry [E. C. M.], and Medicine [C. W.], The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030

Cerebrospinal fluid (CSF) was obtained from five patients by lumbar puncture and from two patients by Ommaya reservoir tap after the i.v. administration of the antitumor agent N-(phosphonacetyl)-L-aspartate (PALA). PALA was quantified enzymatically by inhibition of the target enzyme, aspartate carbamoyltransferase. After a 1-hr infusion of PALA, its CSF concentration steadily rose until the eighth hr, at which time it was 12 to 40% of concurrent plasma concentration. PALA concentration then declined more gradually in CSF than in plasma, and CSF concentrations exceeded plasma concentrations by 24 hr. PALA concentration x time product in CSF was 12 to 25% of that in plasma.

PALA was infused i.v. for 30 to 60 min into eight patients undergoing surgical resection of intracerebral tumors. Its concentration in intracerebral tumor was greater than or comparable to concentration in temporalis muscle in four of six patients from whom muscle was obtained. The PALA concentration in edematous brain tissue was consistently lower than the concentration in tumor or muscle. In a patient undergoing occipital lobectomy, the PALA concentration in brain was inversely proportional to the distance from the tumor. PALA reached concentrations in intracerebral tumor that appeared to be similar to concentrations reported previously in s.c. tumors, although biopsy techniques and conditions differed.

¹ Supported in part by Grant CA-14528 and Contract CM87185 from the National Cancer Institute, NIH, USPHS, Bethesda, Md.

² Junior Faculty Fellow, American Cancer Society. To whom requests for reprints should be addressed.

Received 10/ 3/79. Accepted 6/ 3/80.