Biodistribution of misonidazole and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in rats bearing unclamped and clamped 9L subcutaneous tumors.
The biodistribution of misonidazole (MISO) and 1,3bis(2-chloroethyl)-1-nitrosourea (BCNU) was studied using the subcutaneous (s.c.) 9L tumor model in male Fisher 344 rats. A transient hypoxia in these tumors was created by clamping the blood supply to the tumor. Reoxygenation occurred upon release of the clamp. The plasma and tumor concentrations of MISO and BCNU were quantitated by high pressure liquid chromatography. When 12 mg/kg of BCNU was given i.p. without MISO, the peak plasma concentration was about 6 micrograms/ml, and the elimination half-time was about 16 min. When 2.5 mmole/kg of MISO was given i.p. 150 min before the BCNU, the peak plasma concentration of BCNU increased by approximately 33%, and the plasma elimination half-time increased by approximately 57%. Clamping the tumor for 120 min did not significantly change the BCNU concentration in plasma, but in tumors the time to reach the peak level was delayed slightly, and the peak concentration was reduced when compared to that in the unclamped tumors. MISO pretreatment decreased the BCNU peak concentration in both unclamped and clamped tumors, but the decrease was more pronounced in the unclamped tumors. In both unclamped and clamped tumors, the BCNU concentration and its rate of disappearance were identical about 30 min after BCNU administration, with or without MISO pretreatment. The elimination half-time of MISO from the plasma (approximately 142 min) was identical for rats with unclamped or clamped tumors. The half-time for the disappearance of MISO from unclamped tumors was about 98 min. BCNU had no effect on the MISO concentration in plasma and unclamped tumors. MISO disappeared in the clamped tumors with a half-time of about 40 min. When the clamp was released, the MISO concentration returned to the level in the unclamped tumors after about 45 min. BCNU delayed the return of the MISO concentration to the unclamped tumor level by about 60 min. Two conclusions can be drawn from this study. First, the pharmacokinetics of each drug changed when the two drugs were combined. Second, the data indicate that alterations in the tumor BCNU pharmacokinetics are not the major mechanism responsible for the chemopotentiation previously measured in s.c. 9L tumors.
Wong
K H
KH
Department of Radiology, Wake Forest University Medical Center, Winston-Salem, NC 27103.
Wallen
C A
CA
Wheeler
K T
KT
D000818:Animals; D001682:Biological Availability; D002330:Carmustine / Q000493:pharmacokinetics*; D003250:Constriction; D004347:Drug Interactions; D006207:Half-Life; D008297:Male; D008920:Misonidazole / Q000493:pharmacokinetics*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D012039:Regional Blood Flow; D014018:Tissue Distribution
D008920:Misonidazole; D002330:Carmustine