| Abstract: | To estimate the rate of CCl4 metabolism in vivo by using an inhalation pharmacokinetic approach based on arterial blood:air concentration ratios, the blood CCl4 concentrations (Cart) at the end of 5-hr exposure to varying concentrations of CCl4 in inhaled air (Cinh) were determined in male, naive rats and in rats pretreated with po administration of 100 or 200 microliters CCl4/100 g body weight 24 hr before exposure. Hepatic cytochrome P-450 content during and at the end of exposure was also determined. The biphasic nature of the Cart-Cinh curve for naive rats, with a transition at Cinh of about 100 ppm, indicated that CCl4 metabolism is perfusion-limited below 100 ppm and is saturated above 100 ppm. In 100 microliters CCl4-pretreated rats, Cinh at the transition point decreased from 100 to 50 ppm; this percentage decrease was consistent with the decreased cytochrome P-450 content induced by administration of 100 microliters CCl4. In 200 microliters CCl4-pretreated rats, where CCl4 metabolizing enzyme activity was completely inhibited, the Cart-Cinh curve gave a single line with a shallower slope than that of the steeper part of the curve for naive rats, reflecting a loss of cytochrome P-450 content during exposure. The curves of calculated uptake rate showed continued uptake in completely inhibited rats, representing the contribution of fat loading only. The rate of metabolism was approximated by the uptake rate for naive rats minus that for 200 microliters CCl4-pretreated rats, and decreased gradually with increasing Cinh over the range of saturable metabolism. From this rate curve, Vmax and Km for naive rats were 2.7 mg/kg/hr and of the order of 0.3 mg/liter, respectively. The gradual decrease in the rate of metabolism could be interpreted in terms of the rapid loss of cytochrome P-450 content. The Vmax for 100 microliters CCl4-pretreated rats decreased by about 57%, which was in good agreement with the decrease of cytochrome P-450 content. These experiments suggest the usefulness and validity of this approach for studying metabolism of a volatile compound. |
