Diazepam and N-desmethyldiazepam redistribution after heparin

The effects of heparin, 1,000 U intravenously, on the blood, plasma, and free concentrations of diazepam and its metabolite, N-desmethyldiazepam, have been investigated 3 hr after oral administration of 10 mg diazepam to 5 normal subjects. The percent free diazepam and N-desmethyldiazepam increased 15 min after heparin from 1.66 +/- 0.35 to 3.99 +/- 1.88 (mean +/- SD; p less than 0.05) in the case of diazepam anolite. The actual free concentration of diazepam rose from 3.6 +/- 1.04 to 6.9 +/- 1.33 ng/ml (p less than 0.05) 15 min after heparin while total blood concentration was unchanged (144 +/- 54 vs 130 +/- 57 ng/ml). Free concentrations of N-desmethyldiazepam rose from 0.62 +/- 0.17 to 1.01 +/- 0.34 but the effect, though consistent, was not statistically significant. Blood concentrations did not change (15 +/- 3.2 vs 14 +/- 3.9 ng/ml). That free drug level rose without a change in blood or total plasma levels suggests that factors other than simple plasma binding displacement are involved in this drug interaction.