Influence of method of systemic administration of adenovirus on virus-mediated toxicity: focus on mortality, virus distribution, and drug metabolism.
BACKGROUND
Doses of 2 x 10(12) virus particles/kilogram (vp/kg) and higher of recombinant human adenovirus serotype 5 (HAdV-5) given via the tail vein induce significant toxicity and mortality in the rat. This was not observed when doses of 5.7 x 10(12) vp/kg were given through a surgically implanted jugular catheter. Here we assess how the manner by which HAdV-5 is introduced into the systemic circulation affects biodistribution, transgene expression, toxicity and mortality 0.25, 1, and 4 days after treatment in the rat. Animals were given 5.7 x 10(12) vp/kg of HAdV-5 expressing beta-galactosidase or saline through a jugular catheter or by direct tail vein injection.


RESULTS
All animals survived after jugular vein dosing. Tail vein injection of HAdV-5 increased the mortality rate to 42% (p< or =0.01). All deaths occurred within 4 h. Animals dosed through the jugular vein had significantly higher levels of transgene expression in the liver and spleen and significantly more viral genomes in these tissues and kidney and lung within the first 24 h of viral infection compared to those dosed by tail vein injection (p< or =0.01). There was no significant difference between the groups thereafter. Samples from animals that died contained even higher levels of viral genomes and serum transaminases were elevated on average by a factor of 4 at the time of death. There was no significant difference between the two dosing methods with respect to changes in hepatic cytochrome P450 expression and activity throughout the study.


CONCLUSIONS
These findings suggest that the method of systemic administration should be carefully considered when assessing toxicity data and other parameters at early time points after virus administration in the rat and possibly other animal models.
Boquet
Michael P
MP
The University of Texas at Austin, College of Pharmacy, Division of Pharmaceutics, Austin, TX 78712-1074, USA.
Wonganan
Piyanuch
P
Dekker
Joseph D
JD
Croyle
Maria A
MA
D000256:Adenoviridae / Q000145:classification / Q000235:genetics*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D016679:Genome, Viral / Q000235:genetics; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001616:beta-Galactosidase