Pharmacokinetics and biodisposition of recombinant human interferon-alpha 2C in rat and marmoset.
Pharmacokinetics and biodiposition of recombinant human interferon-alpha 2C (IFN-alpha 2C) were studied in rats and marmosets (Callitrix jacchus). After intravenous bolus dose, serum concentrations of IFN-alpha 2C antigen declined triexponentially. After administration of 15 MIU/kg IFN-alpha 2C the mean t1/2 alpha was 3 min (rat) and 10 min (marmoset), t1/2 beta was 0.4 h (rat) and 1.2 h (marmoset), the mean terminal half-life t1/2 gamma was 2.8-6.3 h (rat) and 10-14 h (marmoset). The short alpha-phase was dominant, consistent with the high total serum clearance of 5 ml/min/kg (rat) or 2 ml/min/kg (marmoset), respectively. The low volumes of distribution (in both species 0.4-0.8 l/kg) indicated a mainly extracellular distribution of this drug. Absolute bioavailability after intramuscular and subcutaneous dosing ranged from 40-80% and the time of maximum serum level from 0.7-2.7 h (both species). Dose linearity was observed up to 15 MIU/kg for all routes of administration. The results demonstrate similarity of IFN-alpha 2C pharmacokinetics in rat and marmoset. Biodisposition of IFN-alpha 2C in rat was determined both by whole body autoradiography and analysis of antigen concentrations in tissue homogenates. The distribution of IFN-alpha 2C antigen showed a high correlation with capillary permeability and blood content of the different tissues. Thus, high levels were found in serum, kidney, lung, spleen, heart and liver, whereas the concentrations in muscle and brain were extremely low. Taken together, the data indicate that IFN-alpha 2C is predominantly eliminated by glomerular filtration, followed by tubular reabsorption, and finally lysosomal degradation in the kidney.
Greischel
A
A
Department of Biochemistry, Dr. Karl Thomae GmbH, Biberach an der Riss, Fed. Rep. of Germany.
Tanswell
P
P
Busch
U
U
Schumacher
K
K
D000818:Animals; D000941:Antigens / Q000032:analysis; D001345:Autoradiography; D001682:Biological Availability; D002144:Callithrix; D006207:Half-Life; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007370:Interferon Type I / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D011994:Recombinant Proteins; D014018:Tissue Distribution
D000941:Antigens; D007370:Interferon Type I; D011994:Recombinant Proteins