PHARMACOKINETICS OF RECONSTITUTED HUMAN HIGH-DENSITY-LIPOPROTEIN IN PIGS AFTER HEMORRHAGIC-SHOCK WITH RESUSCITATION

Objectives: Reconstituted human high density lipoprotein (HDL) can inh ibit lipopolysaccharide effects in vivo, The major objectives of this study were to characterize the pharmacokinetics of reconstituted HDL i n a stressed large-animal model and to provide preclinical tolerance i nformation in support of use of reconstituted HDL in humans. Design: A randomized, blinded, placebo-controlled trial where each animal recei ved either reconstituted human HDL at a dose of 100 mg/kg (apolipoprot ein A-I) or placebo, immediately after hem orrhagic shock acid resusci tation. Setting: Animal laboratory. Subjects: Twelve immature female s wine (18 to 25 kg) were studied. Interventions: Six to 8 days before s hock and study drug administration, animals were anesthetized and cath eters were placed in the external jugular vein and abdominal aorta. Th ese catheters were secured to the dorsal surface. On the day of shock, the animals were sedated (alpha-chloralose) and 50 mL/kg of arterial blood was removed over 0.5 hr, One half hour after blood removal, shed blood was infused, which was immediately followed by study drug (reco nstituted HDL or placebo), and then by 1 L of lactated Ringer's soluti on. Measurements and Main Results: Physiologic (arterial blood pressur e, heart rate, respiratory rate) and laboratory (serum chemistries, he matologic and coagulation studies, and blood gases) measurements were determined intermittently for 96 hrs after the induction of shock, Blo od was collected intermittently for 48 hrs after shock for assay of ap olipoprotein A-I and phosphatidylcholine in plasma. Reconstituted HDL was well tolerated and did not appear to alter the physiologic respons es to shock and resuscitation. HDL transient increase in aspartate ami notransferase concentration was noted in the reconstituted group but t his increase normalized by 24 hrs after drug administration, Mean apol ipoprotein A-I pharmacokinetic parameters were as follows: half-life 2 4.5 +/- 5.3 (SD) hrs; clearance 41.9 +/- 10 mL/hr; and volume of distr ibution 1.39 +/- 0.08 L. The apparent mean half-life of phosphatidylch oline was 5.4 +/- 0.8 hrs. Conclusions: Reconstituted human HDL was we ll tolerated in animals that had undergone hemorrhagic shock with resu scitation. The apolipoprotein component of reconstituted HDL had a rel atively long half-life, with distribution limited to the vascular spac e, These findings support the investigational use of this product in h umans.