Pharmacokinetics of reconstituted human high-density lipoprotein in pigs after hemorrhagic shock with resuscitation

Joseph T. DiPiro, Jorge I. Cue', Calita S. Richards, Michael L Hawkins, Jan E. Doran, Arlie R. Mansberger

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Objectives: Reconstituted human high-density lipoprotein (HDL) can inhibit lipopolysaccharide effects in vivo. The major objectives of this study were to characterize the pharmacokinetics of reconstituted HDL in a stressed large-animal model and to provide preclinical tolerance information in support of use of reconstituted HDL in humans. Design: A randomized, blinded, placebo-controlled trial where each animal received either reconstituted human HDL at a dose of 100 mg/kg (apolipoprotein A-I) or placebo, immediately after hemorrhagic shock and resuscitation. Setting: Animal laboratory. Subjects: Twelve immature female swine (18 to 25 kg) were studied. Interventions: Six to 8 days before shock and study drug administration, animals were anesthetized and catheters were placed in the external jugular vein and abdominal aorta. These catheters were secured to the dorsal surface. On the day of shock, the animals were sedated (α- 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 (reconstituted HDL or placebo), and then by 1 L of lactated Ringer's solution. Measurements and Main Results: Physiologic (arterial blood pressure, heart rate, respiratory rate) and laboratory (serum chemistries, hematologic and coagulation studies, and blood gases) measurements were determined intermittently for 96 hrs after the induction of shock. Blood was collected intermittently for 48 hrs after shock for assay of apolipoprotein A-I and phosphatidylcholine in plasma. Reconstituted HDL was well tolerated and did not appear to alter the physiologic responses to shock and resuscitation. HDL transient increase in aspartate aminotransferase concentration was noted in the reconstituted group but this increase normalized by 24 hrs after drug administration. Mean apolipoprotein A-I pharmacokinetic parameters were as follows: half-life 24.5 ± 5.3 (SD) hrs; clearance 41.9 ± 10 mL/hr; and volume of distribution 1.39 ± 0.08 L. The apparent mean half-life of phosphatidylcholine was 5.4 ± 0.8 hrs. Conclusions: Reconstituted human HDL was well tolerated in animals that had undergone hemorrhagic shock with resuscitation. The apolipoprotein component of reconstituted HDL had a relatively long half-life, with distribution limited to the vascular space. These findings support the investigational use of this product in humans.

Original languageEnglish (US)
Pages (from-to)440-444
Number of pages5
JournalCritical Care Medicine
Volume24
Issue number3
DOIs
StatePublished - Mar 1 1996

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Hemorrhagic Shock
HDL Lipoproteins
Resuscitation
Swine
Pharmacokinetics
Shock
Apolipoprotein A-I
Half-Life
Placebos
Phosphatidylcholines
Catheters
Pharmaceutical Preparations
Chloralose
Apolipoproteins
Abdominal Aorta
Jugular Veins
Laboratory Animals
Blood Coagulation
Respiratory Rate
Aspartate Aminotransferases

Keywords

  • apolipoprot ein A-I
  • critical illness
  • endotoxemia
  • hemorrhage
  • high-density lipoprotein
  • lipopolysaccharide
  • pharmacokinetics
  • resuscitation
  • shock

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Pharmacokinetics of reconstituted human high-density lipoprotein in pigs after hemorrhagic shock with resuscitation. / DiPiro, Joseph T.; Cue', Jorge I.; Richards, Calita S.; Hawkins, Michael L; Doran, Jan E.; Mansberger, Arlie R.

In: Critical Care Medicine, Vol. 24, No. 3, 01.03.1996, p. 440-444.

Research output: Contribution to journalArticle

DiPiro, Joseph T. ; Cue', Jorge I. ; Richards, Calita S. ; Hawkins, Michael L ; Doran, Jan E. ; Mansberger, Arlie R. / Pharmacokinetics of reconstituted human high-density lipoprotein in pigs after hemorrhagic shock with resuscitation. In: Critical Care Medicine. 1996 ; Vol. 24, No. 3. pp. 440-444.
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AU - DiPiro, Joseph T.

AU - Cue', Jorge I.

AU - Richards, Calita S.

AU - Hawkins, Michael L

AU - Doran, Jan E.

AU - Mansberger, Arlie R.

PY - 1996/3/1

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N2 - Objectives: Reconstituted human high-density lipoprotein (HDL) can inhibit lipopolysaccharide effects in vivo. The major objectives of this study were to characterize the pharmacokinetics of reconstituted HDL in a stressed large-animal model and to provide preclinical tolerance information in support of use of reconstituted HDL in humans. Design: A randomized, blinded, placebo-controlled trial where each animal received either reconstituted human HDL at a dose of 100 mg/kg (apolipoprotein A-I) or placebo, immediately after hemorrhagic shock and resuscitation. Setting: Animal laboratory. Subjects: Twelve immature female swine (18 to 25 kg) were studied. Interventions: Six to 8 days before shock and study drug administration, animals were anesthetized and catheters were placed in the external jugular vein and abdominal aorta. These catheters were secured to the dorsal surface. On the day of shock, the animals were sedated (α- 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 (reconstituted HDL or placebo), and then by 1 L of lactated Ringer's solution. Measurements and Main Results: Physiologic (arterial blood pressure, heart rate, respiratory rate) and laboratory (serum chemistries, hematologic and coagulation studies, and blood gases) measurements were determined intermittently for 96 hrs after the induction of shock. Blood was collected intermittently for 48 hrs after shock for assay of apolipoprotein A-I and phosphatidylcholine in plasma. Reconstituted HDL was well tolerated and did not appear to alter the physiologic responses to shock and resuscitation. HDL transient increase in aspartate aminotransferase concentration was noted in the reconstituted group but this increase normalized by 24 hrs after drug administration. Mean apolipoprotein A-I pharmacokinetic parameters were as follows: half-life 24.5 ± 5.3 (SD) hrs; clearance 41.9 ± 10 mL/hr; and volume of distribution 1.39 ± 0.08 L. The apparent mean half-life of phosphatidylcholine was 5.4 ± 0.8 hrs. Conclusions: Reconstituted human HDL was well tolerated in animals that had undergone hemorrhagic shock with resuscitation. The apolipoprotein component of reconstituted HDL had a relatively long half-life, with distribution limited to the vascular space. These findings support the investigational use of this product in humans.

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KW - critical illness

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KW - hemorrhage

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KW - lipopolysaccharide

KW - pharmacokinetics

KW - resuscitation

KW - shock

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