Linear relationship between cytochrome P-450 and carbamazepine clearance in rhesus monkey

The effect of carbamazepine (CBZ) long-term (4-day) infusions on changes in liver cytochrome P-450 levels were examined in eight rhesus monkeys. Each animal received two treatments. Treatment I was a 4-hr CBZ infusion and treatment II was a 4-day CBZ infusion. At the end of each treatment, the monkey was anesthetized and a liver biopsy was taken. The tissue was homogenized and cytochrome P-450 and protein were determined in the crude liver homogenate. During treatment II, blood samples taken at 8 and 101 hr were assayed for CBZ and the clearance of CBZ at these times determined. The mean (+/- SD) CBZ clearance at 8 and 101 hr during treatment II was 0.88 +/- 0.17 and 1.35 +/- 0.34 liters/hr/kg, respectively. The mean (+/-SD) liver cytochrome P-450 level between treatment I and treatment II was 0.26 +/- 0.04 and 0.44 +/- 0.14 nmol/mg of protein, respectively. A high degree of correlation (r2 = 0.85) was observed between the percentage change in cytochrome P-450 and the percentage change in CBZ intrinsic clearance. Theoretical and experimental results suggest a direct quantitative relationship between these parameters.