The effects of antirhino- and enteroviral vinylacetylene benzimidazoles on cytochrome P450 function and hepatic porphyrin levels in mice.
In an ongoing effort to identify an orally bioavailable compound for the treatment of rhino- and enteroviral infections, a series of vinylacetylene benzimidazoles was recently examined. Previous studies demonstrated the potential for these compounds to possess both good in vitro antiviral activity as well as acceptable oral plasma concentrations in mice. Optimization of these properties led to four compounds as candidates for further evaluation. In view of the recognized potential for certain acetylenic drugs both to inhibit cytochrome P450 enzymes by mechanism-based inactivation and to possibly perturb heme metabolism, information regarding drug effects on cytochromes P450 and hepatic porphyrin levels was sought. In an initial single-dose pharmacokinetic study, the four selected compounds were given orally to mice, and both plasma concentrations and porphyrin levels were determined. Two of the compounds, 4 and 5, caused a pronounced increase in liver porphyrin levels whereas compounds 6 and 7 exhibited almost no effect on porphyrin levels. Analysis of plasma concentrations showed that only 4 and 5 gave significant exposure and that 6 and 7 produced negligible levels of drug in the plasma even at the highest dose tested (500 mg/kg). A multiple dose study was then initiated in which compounds 4 and 5 were given for 1 week in daily oral doses to mice. Upon completion of dosing, liver was analyzed for cytochrome P450-dependent 7-ethoxyresorufin O-deethylase (EROD) and benzphetamine N-demethylase (BND) activities, total cytochrome P450 content, and porphyrin levels. Both vinylacetylenes showed dose dependent inhibitory and induction effects on EROD and BND activities. In addition, these compounds caused a marked increase in hepatic porphyrin levels. Therefore, while all four selected compounds displayed potent antiviral activity and two of the compounds exhibited acceptable pharmacokinetic properties, the hepatic effects of these latter two compounds suggest the potential for drug induced porphyria with multidose therapeutic use.
Tebbe
M J
MJ
Infectious Diseases Research, Eli Lilly, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. tebbe_mark_j@lilly.com
Jensen
C B
CB
Spitzer
W A
WA
Franklin
R B
RB
George
M C
MC
Phillips
D L
DL
D000114:Acetylene / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004770:Enterovirus / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011166:Porphyrins / Q000378:metabolism*; D012229:Rhinovirus / Q000187:drug effects*
D000998:Antiviral Agents; D001562:Benzimidazoles; D011166:Porphyrins; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating; D000114:Acetylene