Mass kinetics of apolipoprotein A-I in interstitial fluid after administration of intravenous apolipoprotein A-I/lecithin discs in humans

C. Justin Cooke,Waldemar L. Olszewski,Irina P. Miller,Roman Hovorka,M. Nazeem Nanjee,Norman E. Miller

doi:10.1194/jlr.m500358-jlr200

Abstract

Apolipoprotein kinetics are customarily determined by modeling time curves of specific radioactivity or isotopic enrichment in plasma after intravenous infusion of radiolabeled lipoproteins or stable isotope-enriched amino acids. However, this provides no information on the fractional rate of transfer of the apolipoprotein from plasma to interstitial fluid (k(p-if)) or its mean residence time in interstitial fluid (MRT(if)). To determine these parameters for a pharmacologic dose of exogenous apolipoprotein A-I (apoA-I) given intravenously as apoA-I/lecithin discs, we measured apoA-I in plasma and prenodal leg lymph in five healthy men before, during, and after a 4 h infusion at 10 mg/kg/h. ApoA-I concentrations in plasma and lymph were modeled by linear compartmental models (SAAM II version 1.1), using lymph albumin to adjust for the effects of variations in lymph flow rate. k(p-if) averaged 0.75%/h (range, 0.33-1.32), and MRT(if) averaged 29.1 h (14.1-40.0). Neither parameter was correlated with the distribution volume (57-105 ml/kg) or the fractional elimination rate (1.44-2.91%/h) of apoA-I, determined by modeling plasma apoA-I concentration alone. Although used here to study the mass kinetics of apoA-I, if combined with infusion of a tracer, analysis of lymph could also expand the modeling of endogenous apolipoprotein kinetics.

Highlights

Apolipoprotein kinetics are customarily determined by modeling time curves of specific radioactivity or isotopic enrichment in plasma after intravenous infusion of radiolabeled lipoproteins or stable isotope-enriched amino acids
We have applied this technique to study the pharmacokinetics of exogenous apolipoprotein A-I in interstitial fluid (IF) after intravenous infusion of apoA-I/lecithin discs, a procedure of current interest as a potential new therapy for coronary heart disease [9, 10]
IF, interstitial fluid. a Determined from plasma concentration-time curve. b Determined from plasma and lymph concentration-time curves

Summary

Introduction

Apolipoprotein kinetics are customarily determined by modeling time curves of specific radioactivity or isotopic enrichment in plasma after intravenous infusion of radiolabeled lipoproteins or stable isotope-enriched amino acids This provides no information on the fractional rate of transfer of the apolipoprotein from plasma to interstitial fluid (kp-if) or its mean residence time in interstitial fluid (MRTif). Apolipoprotein kinetics are customarily determined either by modeling the plasma specific radioactivity-time curve after intravenous injection of radioiodinated lipoprotein or by infusing a stable isotope-enriched amino acid and modeling its appearance in the apolipoprotein in plasma by mass spectrometry Both procedures have provided much valuable information [1,2,3,4,5]. We have applied this technique to study the pharmacokinetics of exogenous apolipoprotein A-I (apoA-I) in IF after intravenous infusion of apoA-I/lecithin discs, a procedure of current interest as a potential new therapy for coronary heart disease [9, 10]

Methods

Results

Conclusion