Drug-virus interaction: effect of administration of recombinant adenoviruses on the pharmacokinetics of docetaxel in a rat model.
Modern cancer therapy combines recombinant viruses with traditional chemotherapeutic agents that are metabolized by hepatic cytochrome P450 3A4 (CYP3A4). A single dose of recombinant adenovirus (Ad) expressing beta-galactosidase (AdlacZ) significantly alters CYP3A2, the correlate of CYP3A4, in rats for 14 days. Recombinant adenovirus expressing human p53 (Adp53) also suppresses CYP3A2. Plasma clearance of docetaxel (DTX) in animals given AdlacZ (3.38+/-0.22 l h(-1) kg(-1)) was significantly lower than that of those given DTX alone (7.35+/-1.22 l h(-1) kg(-1), P<or=0.05). Area under the plasma concentration-time curve of DTX in rats given AdlacZ (2987.37+/-197.97 ng ml(-1) h(-1)) was significantly greater than those given drug alone (1496.14+/-281.62 ng ml(-1) h(-1), P<or=0.05). Both viruses prolonged DTX half-life (t(1/2)). Ad infection may cause significant variability in the pharmacokinetics and pharmacodynamics of anti-cancer agents and should be considered when designing therapeutic regimens for patients with viral infection and those enrolled in clinical trials using recombinant viruses.
Wonganan
P
P
Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712-1074, USA.
Zamboni
W C
WC
Strychor
S
S
Dekker
J D
JD
Croyle
M A
MA
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004195:Disease Models, Animal; D000077143:Docetaxel; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000493:pharmacokinetics*; D000637:Transaminases / Q000097:blood
D000972:Antineoplastic Agents, Phytogenic; D065607:Cytochrome P-450 Enzyme Inhibitors; D008565:Membrane Proteins; D043823:Taxoids; D000077143:Docetaxel; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000637:Transaminases