title: 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 mice.
abstract: 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 micrograms.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.h/ml and a half-life of 4.9 h. In this human, the Cmax 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.
authors.affiliation: Stehlin Foundation for Cancer Research, St. Joseph Hospital, Houston, Texas 77003.
authors.forename: H R
authors.initials: HR
authors.lastname: Hinz
authors.forename: N J
authors.initials: NJ
authors.lastname: Harris
authors.forename: E A
authors.initials: EA
authors.lastname: Natelson
authors.forename: B C
authors.initials: BC
authors.lastname: Giovanella
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: C080125:9-aminocamptothecin; C079905:rubitecan; D002166:Camptothecin