Pharmacokinetics of Recombinant Leukocyte A Interferon Following Various Routes and Modes of Administration to the Dog

Abstract

The pharmacokinetics of recombinant leukocyte A interferon (rIFN-alpha A) were studied following intravenous (i.v.) bolus, 60 min (i.v. inf.) infusion, intramuscular (i.m.), subcutaneous (s.c.), and oral (p.o.) administrations to 15 male beagle dogs. Each animal received at least one 3 X 10(6) units/kg dose of rIFN-alpha A by one of the five routes and/or modes of administration. Blood samples were collected and the serum was separated and analyzed for rIFN-alpha A concentrations by an enzyme immunoassay, ELISA. There were no measurable rIFN-alpha A concentrations (less than 0.020 ng/ml) following oral administration. In general serum rIFN-alpha A concentrations exceeded 100 ng/ml following i.v. bolus and infusion doses then declined rapidly in a biphasic manner. The volume of distribution at steady state Vdss ranged from 0.14 to 0.21 liters/kg after i.v. infusion. Total body serum clearance (ClB) ranged from 14.6 to 23.9 ml/min, which is about 50% the estimated inulin clearance in dogs. The harmonic mean elimination half-lives ranged from 4.5 to 9.5 h. A prolonged absorption profile was seen following i.m. and s.c. administrations and the systemic bioavailability for both routes was 42% when compared with the i.v. infusion. These appear to be the first pharmacokinetic profiles of rIFN-alpha A reported in the dog.

Ingested IFN-α

“…Type I IFN is acid-stable and resists preprandial stomach acidity. 39 Oral administration of IFN-␣ to mice, 39 rabbits, 40 dogs, 41 monkeys, 42 and humans in doses sometimes exceeding 1 billion IU do not result in detectable levels of IFN-␣ in the blood. 35,36 Type I IFN receptors are found on all lymphoid cells, including those of the gut-associated lymphoid tissue.…”

Antinociceptive Activity of Stephanolepis hispidus Skin Aqueous Extract Depends Partly on Opioid System Activation

“…Another possibility is that the active component present in the SAE has a protein profile. The lack of measurable serum concentrations of proteic drugs, including Interferon, following oral administration was not unexpected since degradation of proteins in the gastrointestinal tract is a natural process of digestion [20]. …”

Oromucosal Administration of Interferon to Humans

“…Several early pharmacokinetic studies of IFNα given by various routes to animals reported that "orally" administered IFNα was not detectable in the systemic circulation [6,7,8,9,10]. However, the investigators of these studies did not deliver the IFNα by the oral mucosal route.…”