Disposition of drugs in cystic fibrosis. VII. Acetylation of sulfamethoxazole in blood cells: in vitro-in vivo correlation and characterization of its kinetics of acetylation in lymphocytes.

Objective: To determine if acetylation of sulfamethoxazole in blood cells is a surrogate measure of its acetylation in vivo. If it is, to use these cells to determine the mechanism(s) by which acetylation of sulfamethoxazole is enhanced in cystic fibrosis.

Methods: Single-point sulfamethoxazole acetylation activity in blood cells obtained from patients with cystic fibrosis (n = 6) and control subjects (n = 7) who had previously participated in our in vivo study was determined. The parameters, Vmax and Km, for acetylation of sulfamethoxazole in lysed lymphocytes obtained from patients with cystic fibrosis (n = 6) and control subjects (n = 5) were also determined.

Results: The acetylation activity in cystic fibrosis whole blood, lysed erythrocytes, and lysed peripheral blood mononuclear cells was significantly (p < 0.05) greater than that in cells obtained from control subjects and was highly correlated with acetylation of sulfamethoxazole in vivo (r > 0.80). The apparent Vmax for cystic fibrosis lymphocyte lysate was significantly (p < 0.05) greater than that obtained for control lymphocyte lysate (72.99 +/- 9.07 versus 60.97 +/- 2.26 pmol/mg protein/min), and the apparent Km was significantly (p < 0.05) lower (0.51 +/- 0.07 versus 0.73 +/- 0.06 mmol/L).

Conclusion: Blood cells may be used as surrogate markers to elucidate the mechanism(s) by which acetylation of sulfamethoxazole (catalyzed by the monomorphic N-acetyltransferase) is enhanced in subjects with cystic fibrosis. Both activation or activation and induction of the monomorphic N-acetyltransferase should be considered as possible mechanism(s) to explain this phenomenon.