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Pharmacokinetics of the in Vivo and in Vitro Conversion of 9-Nitro-20(S)-camptothecin to 9-Amino-20(S)-camptothecin in Humans, Dogs, and Mice¹

The Stehlin Foundation for Cancer Research at St. Joseph Hospital, Houston, Texas 77003

We have determined that 9-nitro-20(S)-camptothecin (9NC) converts to 9-amino-20(S)-camptothecin (9AC) in humans, dogs, and mice. Following a single oral dose of 0.1 mg/kg of 9NC, the human plasma concentration reached a maximum concentration of 483 ng/ml at 3.4 h with an area under the curve (AUC) of 2.6 µg·h/ml and a half-life of 2.5 h. As conversion of 9NC to 9AC occurred, the maximum calculated concentration of 9AC was 14.0 ng/ml at 10.3 h with an AUC of 311 ng·h/ml and a half-life of 7.1 h. Following a single oral dose of 1.0 mg/kg of 9NC, the maximum concentration of 9NC in the human volunteer was 1247 ng/ml at 5.3 h with an AUC of 17194 ng·/ml and a half-life of 4.9 h. In this human, the C_max of 9AC was 208 ng/ml at 17.2 h; the AUC was determined to be 9121 ng·h/ml, and the half-life was 13.1 h.

In a dog after a single oral dose of 1.0 mg/kg 9NC, the maximum concentration for 9NC was 19.1 ng/ml at 0.7 h with a half-life of 6.4 h and an AUC of 186 ng·h/ml. The maximum concentration of 9AC in this dog was 9.2 ng/ml at 2.9 h with an AUC of 310 ng·h/ml and a half-life of 21.1 h.

The maximum concentration of 9NC in the mouse after a single oral dose of 4.1 mg/kg of 9NC was 732 ng/ml at time 0.1 h with an AUC of 441 ng·h/ml and a half-life of 10.0 h. The maximum concentration of 9AC in the mouse was 26 ng/ml at 0.6 h. The AUC was 63 ng·h/ml, and the half-life was 1.2 h.

Incubation of mouse liver, spleen, kidney, brain, and muscle tissue with 9NC all indicated conversion to 9AC, yet no conversion was observable in cell-free plasma from human or mouse blood. Structural identification of 9AC was confirmed by mass spectrometry.

¹ This work was supported by funds from The Stehlin Foundation for Cancer Research.

² To whom requests for reprints should be addressed, at The Stehlin Foundation for Cancer Research, 1315 Calhoun Street, Suite 1818, Houston, TX 77003.

Received 2/25/94. Accepted 5/ 4/94.

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