PHARMACOKINETICS AND SIDE-EFFECTS OF PERFLUOROCARBON-BASED BLOOD SUBSTITUTES

Perfluorochemicals are fluorine-saturated carbon-based molecules which demonstrate utility in the areas of imaging and oxygen delivery. In g eneral, these molecules are biologically inert and, therefore, do not pose toxicologic risk from metabolic degradation. Intravenous (i.v.) p erfluorocarbon (PFC) emulsions are cleared from the blood through a pr ocess involving phagocytosis of emulsion particles by reticuloendothel ial macrophages (RES) and ultimate elimination through the lung in exp ired air. RES phagocytosis of PFC emulsion particles leads to characte ristic, predictable, and reversible biological effects that are a cons equence of a normal host-defense mechanism. This mechanism is characte rized by dose-related stimulation of macrophages and subsequent releas e of intracellular products (particularly metabolites of the arachidon ic acid cascade and cytokines) which are responsible for most of the b iological effects associated with i.v. PFC emulsions (i.e., cutaneous flushing and fever at lower doses, and macrophage hypertrophy and recr uitment at higher doses). These biological effects are reversible, and do not result in any permanent tissue alteration, even with prolonged exposure at relatively high doses. The rate of PFC elimination from t he RES is proportional to the vapor pressure of the PFC, inversely pro portional to molecular weight and positively influenced by lipophilici ty. This dose-dependent respiratory excretion occurs with no evidence of metabolic products. Repeated administration of high doses of PFC em ulsion may lead to a saturation of the RES-mediated clearance capacity , resulting in a redistribution of PFC to non-RES tissues and ingestio n by resident or mobile macrophages. This condition is benign with res pect to the integrity of the surrounding parenchyma, as well as to the macrophages themselves. Increased pulmonary residual volume (IPRV) du e to pulmonary gas (air) trapping, a reversible side effect, has been observed with i.v. doses of PFC emulsion in some animal species. The g ross morphological change associated with IPRV is not accompanied by a ny histological alteration other than the appearance of vacuolated mac rophages (characteristic of the normal clearance mechanism) and some m inor, increased interalveolar cellularity. Animal lungs affected by IP RV have a normal, pale pink appearance with no visible lesions or sign s of edema. The degree of IPRV is dependent on species, PFC dose, and type of PFC administered; PFCs with higher vapor pressures produce the most severe cases of IPRV in sensitive species. Species sensitivity d epends upon physiological and morphological characteristics. There is no evidence indicating that IPRV occurs in humans. Although i.v. PFC e mulsions may elicit minor untoward effects, these effects are reversib le and, at clinically relevant doses, do not pose a toxicologic risk.