Altered hepatic cytochrome P450 3A4 activity following surgical stress

NTRODUCTION: Cytochrome P450 3A4 (3A4) is a crucial drug-metabolizing enzyme and perturbations in activity due to the stress response may result in pharmacokinetic changes. The effects on 3A4 activity of three surgical procedures were studied. METHODS: 16 patients post AAA repair (A;n=5), colectomy (C;n=6), or peripheral vascular surgery (P;n=5) were studied pre-op, 24, 48, & 72 hrs post-op. 3A4 activity was determined by C14-erythromycin breath test (ERMBT). Correlates of surgical stress, including TNF-α, IL-1β, and IL-6, fluids, and OR times were measured. Data are reported as mean±SEM. ANOVA with SNK test determined significance. RESULTS: The P group had least surgical stress(table)and the smallest decrease in 3A4 activity. A and C groups showed a greater supression of 3A4 activity. TNF-α and IL-1β levels were undetectable. IL-6 levels were associated with more invasive surgery. Although IL-6 was higher in the A and C groups, no major correlation between plasma levels of cytokines and altered 3A4 activity could be demonstrated. One colon was excluded due to an unusual inflammatory response. CONCLUSIONS: Clinical indicators of surgical stress were compared to the maximal decrease in ERMBT. The greater the surgical stress the greater the decrease in ERMBT. Although a linear correlation between IL-6 and Max dERMBT was not found, the higher the IL-6 level, the greater the Max dERMBT. Given that plasma levels of TNF-a and IL-1b were not detected it seems plausible that a greater stress is necessary to use plasma level as a marker of an effect more likely regulated at the tissue level. We intend to evaluate this hypothesis in an animal model of sepsis rather than surgery. Age OR Time EBL(min) OR fluids Peak IL-6 Max dERMBT (min) (liter) (pg/ml) A 70±2 194±29 1400±273*1 8.4±0.9*1 197.7±32.4*74.0±4.2*C 71±7 162±20 475±118 3.7±0.4*291.0±80. 1*59.2±8.1*P 60.5 100±26 170±87 1.5±0.4 77.6±27.4 33.2±9.4 dERMBT=% change from baseline;*p≤0.05 for P; 1 p≤0.05 for C.

Duke Scholars

Author Cynthia Keene Shortell Surgery, Vascular and Endovascular Surgery