The oxygen-carrying resuscitation fluids, Fluosol DA 20% and stroma-free hemoglobin, are currently being evaluated for efficacy and effects in vivo. Because these fluids may be administered to trauma victims, the pharmacokinetics of morphine was studied in rats after transfusion with one of these fluids. During development of high-performance liquid chromatography assay for morphine in plasma, an in vitro interaction between plasma, Fluosol DA, or stroma-free hemoglobin and morphine was observed at pH greater than 10.5. This interaction was dependent on pH and was specific to morphine, compared with codeine. The interaction between stroma-free hemoglobin and morphine appeared to be covalent in nature. The t1/2 of morphine was significantly prolonged from 1.02 +/- 0.50 hours (mean +/- SD) to 2.46 +/- 2.68 hours (p = 0.03) after transfusion with stroma-free hemoglobin, and to 2.05 +/- 0.95 hours (p = 0.006) after transfusion with Fluosol DA. The volume of distribution was increased from 1.35 +/- 0.81 L X kg-1 to 2.99 +/- 1.45 L X kg-1 (p = 0.004) after transfusion with stroma-free hemoglobin; no such difference was observed after transfusion with fluosol DA (p = 0.86). The area under the time-concentration curve was increased from 2.37 +/- 1.78 mg X hr X L-1 to 6.02 +/- 6.61 mg X hr X L-1 (p = 0.02), and total body clearance was decreased from 1.02 +/- 0.53 L X hr-1 X kg-1 to 0.55 +/- 0.36 L X hr-1 X kg-1 (p = 0.01) after transfusion with Fluosol DA. No significant differences were observed in these parameters after transfusion with stroma-free hemoglobin (p = 0.48 and p = 0.81, respectively). These data show that stroma-free hemoglobin prolongs the t1/2 of morphine by altering the volume of distribution. In contrast, Fluosol DA prolongs the t1/2 of morphine by altering the total body clearance. These data may have important therapeutic implications.