The n-3 to n-6 fatty acid ratio determined the immunoregulatory potential of intravenous fat emulsions in vivo. Both n-3 and n-6 fatty acids were immunosuppressive when applied as the main polyunsaturated fatty acid sources. PBMC cytokine release was significantly reduced in these groups. The more balanced the n-3 to n-6 ratios, the less immunosuppressive the fat emulsion. There was no immunosuppressive effect at an n-3 to n-6 ratio of 1:2.1.

No abstract

In the commercially available intravenous formulation of Cyclosporin A (Sandimmun), polyoxyethylated castor oil (Cremophor EL) is used as a solubilizing agent. We have recently reported that the acute nephrotoxic effect of this preparation was alleviated by replacing Cremophor EL with a soybean oil-based fat emulsion in a rat model. To further explore the potential of fat emulsions as carriers for cyclosporin A, data on the in vivo pharmacokinetics and tissue distribution are required. In this study in pigs, the pharmacokinetics of soybean oil-cyclosporin A was compared to that of Sandimmun. The two formulations seemed bioequivalent, as there were no significant differences in the systemic clearances, volumes of distribution or elimination half-lives. Moreover, the tissue distributions of soybean oil-cyclosporin A and Sandimmun were compared in rats. These studies also included two additional lipid-based carriers: one based on iodized ester of poppy seed oil and the other on a liposomal preparation. The tissue distributions were found to be similar regardless of the carriers used. Fat emulsion carriers seem to offer possibilities for preparing better tolerated intravenous formulations of cyclosporin A while maintaining the same characteristics concerning pharmacokinetics and tissue distribution.

Hintergrund: Am Modell der heterotopen Rattenherzallotransplantation haben wir bereits gezeigt, daβ intravenöse Fettemulsionen in Abhängigkeit von ihrem n-3/n 6-Fettsäureverhältnis abgestuft von immunsuppressiv bis immunneutral wirken. Distelöl (n-3:n-6 = 1:370), Fisch- (7,6:1) und Sojaöl (1:6,5) verlängerten die Trans-plantatüberlebenszeit auf 13,3, 12,3 und 10,4 Tage gegenüber 6,7 Tagen (1:2,1 = 01-kontrollgruppe) bzw. 7,8 Tagen (Kochsalzkontrollgruppe) (p < OOl). In der vor-liegenden Untersuchung wird die Modifikation der Abstoβungszeit mit immunhisto-logischen, zellbiologischen und biochemischen Variablen korreliert. Material und Methodik: 20%ige Emulsionen von Distel-, Fisch-, Sojaöl bzw. einer l:l-Mischung von Distel- und Fischöl (Ölkontrollgruppe) wurden unmittelbar nach der Transplantation kontinuierlich infundiert (9 g Fett/kg Körpergewicht/Tag; n = 10 pro Gruppe). Subpopulationen der infiltrierenden und zirkulierenden immunkompetenten Zellen und die Leukotrien-B4- bzw. -B5-Ausschüttung zirkulierender mononukleärer Zellen wurden zu einem definierten Zeitpunkt (4. postoperativer Tag) analysiert. Ergebnisse: In den beiden Gruppen mit der höchsten Überlebenszeitverlängerung war die Zahl infiltrierender Zellen um bis zu 40% reduziert. In der Fischölgruppe waren zudem die zirkulierenden T-Zellen signifikant vermindert. Leukotrien B4 wurde in alien Gruppen in gleicher Menge, Leukotrien B5 ausschlieβlich in der Fischölgruppe sezerniert. Schluβfolgerungen: Intravenöse Fettemulsionen wirken in Abhängigkeit vom n-3/n 6-Fettsäureverhältnis unterschiedlich immunmodulierend. Sowohl n-6- als auch n-3-Fettsäuren wirken im Überschuβ durch Reduktion der Infiltration und Mobilisation immunkompetenter Zellen immunsuppressiv, n-3-Fettsäuren auch durch Pro-duktion von Leukotrien B5. Sojaöl mit einem ausgewogeneren n-3/n-6-Verhältnis als Distelöl ist signifikant weniger immunsuppressiv, und Fettemulsionen mit einem n-3/n-6-Verhältnis von 1:2 sind immunologisch neutral.

The effect on allograft survival of intravenous fat emulsions that differed in the ratio of functionally important n-3 and n-6 fatty acids was studied in a heterotopic cardiac transplant model in rats. Twenty percent fat emulsions were administered by continuous infusion at a dosage of 9 g fat/kg body weight per day, starting immediately after transplantation and continuing until complete rejection. The n-6 and n-3 fatty acids represent 75%, 43%, 60%, and 59% of all fatty acids in safflower oil, fish oil, soybean oil, and a 1:1 mixture of safflower and fish oil, respectively. The n-6 fatty acids predominate in safflower oil (370/1) and soybean oil (6.5/1), while the n-3 fatty acids dominate in the fish oil (7.6/1). The 1:1 mixture of safflower and fish oil has the balanced composition (n-6/n-3 = 2.1/1) recommended by Kinsella and served as oil-treated controls. Continuous infusion of safflower oil, fish oil, and soybean oil prolonged graft survival time to 13.3, 12.3, and 10.4 days, respectively, compared to 6.8 days in the oil-treated controls (P < 0.01 for all comparisons). Another control group infused with saline rejected the allografts after 7.8 days (P = NS compared to oil-treated controls; P < 0.01 for all other comparisons). The data suggest that intravenous administration of polyunsaturated fat emulsions results in an immunosuppressive effect that seems to be dependent on the n-3/n-6 fatty acid ratio of the fat emulsion.(ABSTRACT TRUNCATED AT 250 WORDS)