A potent inhibitory effect of erythromycin and other macrolide antibiotics on the mono-N-dealkylation metabolism of disopyramide with human liver microsomes.

Clinical observation has suggested that erythromycin (EM) may cause an elevation in plasma disopyramide (DP) concentrations and thereby cause potentially fatal arrhythmias in certain patients. To determine whether EM would interfere with the in vivo pharmacokinetics of DP and whether other macrolides would share this action with EM, the effects of EM and other macrolide antibiotics on the in vitro DP metabolism to its major metabolite, mono-N-dealkyldisopyramide, were studied with human liver microsomes obtained from eight patients who underwent partial hepatectomy. The mono-N-dealkylation of DP proceeded with a biphasic enzyme kinetic profile, suggesting that at least two distinct enzyme sites or components are involved in the DP metabolism in humans. The high- and low-affinity sites gave the mean (+/- S.D.) Km of 5.7 +/- 2.8 and 724.7 +/- 427.4 microM, and Vmax of 2.90 +/- 1.17 and 18.20 +/- 8.84 nmol/hr/mg protein, respectively. Because the mean intrinsic clearance (i.e., Vmax/Km) for the high-affinity site (i.e., 0.79 +/- 0.69 ml/hr/mg protein) was about 30 times greater than that for the low-affinity site (i.e., 0.03 +/- 0.01 ml/hr/mg protein), the high-affinity site was considered more important in the DP metabolism at its therapeutic concentrations (i.e., 2-5 micrograms/ml or 5-14 microM). EM inhibited the high-affinity site activity in a noncompetitive manner with the mean Ki of 19.5 +/- 1.3 microM (n = 4). An EM concentration associated with a 50% suppression of the DP metabolism at 30 microM (i.e., IC50) was 94 microM.(ABSTRACT TRUNCATED AT 250 WORDS)