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The perfluorochemical components of synthetic oxygen transporting emulsions may persist in hepatic tissue. After a single 30% blood exchange with the perfluorochemical emulsion, Fluosol-DA 20%, the effects on the microsomal metabolism of 7-methoxycoumarin and 7-ethoxycoumarin were studied over a 9-week period. Fluosol-DA treated animals were compared with controls (sham) and hetastarch-treated controls. Changes in dealkylase activities were compared with induction by phenobarbitone and 3-methylcholanthrene. The liver to body weight ratio increased by 49% in Fluosol-DA-treated rats over the controls at 1 week and the microsomal protein was increased in the Fluosol-DA-treated rats after 4 and 9 weeks. Fluosol-DA treatment induced 7-methoxycoumarin demethylase with peak differences occurring at 1 week and a Vmax 75% greater than controls. Fluosol-DA was a more potent inducer of demethylase than phenobarbitone. In addition, 7-ethoxycoumarin de-ethylase was induced by Fluosol-DA with a peak induction at 4 weeks. The Vmax at 4 weeks in Fluosol-DA-treated rats was 122% greater than control. In this case, Fluosol-DA produced less induction in de-ethylase than 3-methylcholanthrene. These studies show that Fluosol-DA induces more than one form of cytochrome P450 and the effects resemble those of phenobarbitone more than those of 3-methylcholanthrene. Hetastarch, a plasma expander, did not affect liver weights, microsomal protein content, or the cytochrome P450 system.

Perfluorochemical (PFC) emulsions have been examined for use as erythrocyte substitutes in the treatment of various disease states. The physiological changes induced by PFC infusion would be an important determinant of successful clinical therapy. Previous studies have reported PFC induced changes in the disposition of drugs. This report describes some physiological (hematology, cardiovascular, liver enzyme) changes resulting from a 30% blood exchange with a PFC emulsion in Beagle dogs. A 30% blood exchange with hydroxyethylstarch (HES) also was evaluated and compared to the PFC emulsion exchange. The blood pressure was markedly reduced shortly after PFC infusion while HES infusion produced only minor changes. Changes in the heart rate following blood replacement were similar for PFC and HES treated dogs. Hematology profiles also were similar for the PFC and HES treatment groups. The liver enzyme levels in PFC treated dogs showed marked elevations beginning shortly after PFC infusion and remained elevated for months after the initial PFC blood replacement. In contrast, HES treated dogs exhibited no observable changes in liver enzyme levels over the time course of the study.

Perfluorochemical (PFC) emulsions have recently been investigated for use in the treatment of various clinical conditions requiring red blood cell replacement. The physiological changes which develop following PFC infusion may directly, or indirectly alter the disposition of concomitantly administered agents. This study examined the in vitro metabolism of lidocaine (LC) following pretreatment of rats with a PFC emulsion. Studies were conducted from 2 days to 6 months after initial blood replacement. The control treatment included rats that received a blood exchange with their own blood (SHAM). Analysis of LC and its metabolites was performed using solid phase extraction (SPE) and a modified high performance liquid chromatography (HPLC) method. The predominate metabolite observed in the liver slice preparation was monoethylglycinexylidide (MEGX). No glycinexylidide (GX) was noted in any of the treatments. The results indicate an increase in the in vitro rate of metabolism of LC in rats pretreated with the PFC emulsion. These effects appeared to be time-dependent with maximal increase in metabolism at approximately 5 weeks after the blood exchange and persisting for up to 6 months. These changes in the disappearance of LC in liver slice preparations may reflect PFC-induced enzyme induction and/or altered tissue uptake of LC.

At 37 degrees C, valproic acid was weakly bound by a PFCE through an interaction with the emulsifiers that was independent of both buffer and PFCE concentration. The binding by PFCE was dependent on valproic acid concentration in 0.1 M buffer, but not in 0.2 M buffer. The addition of PFCE to 4% HSA increased the percent free valproic acid due to both HSA dilution and displacement of HSA bound drug. This displacement was apparently due to an interaction with the PFC liquids and/or intact PFCE droplets, and with the oleic acid component of the PFCE.

As a result of their ability to transport oxygen, PFC emulsions are being investigated for possible use in a wide variety of conditions. The recent FDA approval of F-DA to diminish myocardial ischemia during angioplasty is the first marketing approval for such a product in the world. The many potential uses of such products may result in their common application in the future, especially as new and better products are developed. The elimination, distribution, and tissue retention of PFC emulsions as well as the physiological changes that occur upon their administration have been the subject of many investigations. The results indicate that these agents may influence the pharmacokinetic properties of other drugs by a wide variety of mechanisms. Several studies have shown significant, but not necessarily consistent, changes in drug elimination and distribution following PFC emulsion infusion. Changes appear dependent on the drug examined, emulsion utilized, degree of blood exchange, species utilized, and the controls chosen for comparison. Often, the changes are time dependent indicating the importance of conducting long-term studies. While PFC emulsions do not appear to alter renal elimination of drugs, several studies have demonstrated that these agents have the potential to induce drug metabolism from several days to possibly months after exposure. Observed changes in drug volumes of distribution, which are often time dependent, may be due to changes in normal drug transport throughout the circulation and/or changes in membrane permeability and cell transport mechanisms. Changes in drug transport may result from depletion of plasma proteins or increases in alpha 1-acid glycoprotein levels due to trauma or PFC emulsion effects. The binding of drugs by PFC emulsion droplets varies greatly and PFC emulsion components displace some plasma protein bound drugs. The wide variability in the results and conclusions of the pharmacokinetic studies conducted to date emphasize the importance of utilizing adequate controls to identify which alterations are PFC emulsion specific.

The effect of a perfluorochemical blood substitute on ligand binding by human albumin was examined using warfarin as a model drug. Binding of warfarin by four per cent human albumin solutions diluted with either buffer or blood substitute, and by blood substitute diluted with buffer was examined. Solutions containing 2 or 10 micrograms/ml warfarin were quantitated by liquid scintillation counting using 14C-warfarin. The per cent warfarin free at room temperature was determined by centrifugation followed by supernatant ultrafiltration. Warfarin was weakly bound by the blood substitute and the overall effect of albumin dilution with the blood substitute was an increase in per cent warfarin free. Blood substitute binding of warfarin may explain the decrease of per cent warfarin free observed when albumin solutions were diluted to 50 and 75% v/v with blood substitute rather than buffer. However, the per cent warfarin free increased when albumin solutions were diluted to 25% v/v with blood substitute rather than buffer. The fraction free increased by 39.0% and 30.4% at total warfarin concentrations of 2 and 10 micrograms/ml, respectively. This relative increase in per cent warfarin free may be the result of a direct and/or indirect displacement of albumin bound warfarin by a component(s) of the blood substitute.