title: The role of liver and kidney on the pharmacokinetics of a recombinant amino terminal fragment of bactericidal/permeability-increasing protein in rats.
abstract: OBJECTIVE
  The pharmacokinetics of rBPI23, a recombinant amino terminal fragment of bactericidal/permeability-increasing protein that binds to and neutralizes endotoxin, was investigated.
  
  
  METHODS
  rBPI23 was administered to rats at doses 0.01-10 mg/kg and plasma rBPI23 levels were measured by ELISA. rBPI23 was also administered to bilaterally nephrectomized rats. In addition, rBPI23 was administered intra-hepatically via the pyloric vein to determine the first-pass effect by the liver. rBPI23 concentrations were also simultaneously measured in the right atrium and aorta to determine the removal of rBPI23 by the lungs.
  
  
  RESULTS
  The concentration-time profile of rBPI23 was described by a 3-compartmental model with parallel first order and Michaelis-Menten (saturable) elimination. The clearance of rBPI23 was not altered by bilateral nephrectomy. Clearance of intra-hepatically administered rBPI23 was 4.5 fold lower than intra-femorally administered rBPI23. The concentration difference of rBPI23 between aortic and right atrial blood was no greater than 11%. Clearance of rBPI23 in rats could be reduced up to 10 fold by co-administration of heparin. Uptake by liver of intra-hepatically administered rBPI23 was prevented by co-administration of heparin.
  
  
  CONCLUSIONS
  rBPI23 is not significantly cleared by the kidneys, and no more than 11% of the rBPI23 was removed by the lungs with each pass. The liver could remove 78% of the rBPI23 from the hepatic circulation. Studies with heparin suggest rBPI23 is cleared by binding to heparan sulfate sites in the liver.
authors.affiliation: Department of Pharmacology, XOMA Corporation, Berkeley, California 94710, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bauer
authors.forename: K
authors.initials: K
authors.lastname: Der
authors.forename: N
authors.initials: N
authors.lastname: Ottah-Ihejeto
authors.forename: J
authors.initials: J
authors.lastname: Barrientos
authors.forename: A H
authors.initials: AH
authors.lastname: Kung
mesh_terms: D000818:Animals; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D008565:Membrane Proteins; D011994:Recombinant Proteins; C025357:endotoxin binding proteins; D006493:Heparin