The effects of antirhino- and enteroviral vinylacetylene benzimidazoles oncytochrome P450 function and hepatic porphyrin levels in mice

In an ongoing effort to identify an orally bioavailable compound for the tr eatment of rhino- and enteroviral infections, a series of vinylacetylene be nzimidazoles was recently examined. Previous studies demonstrated the poten tial for these compounds to possess both good in vitro antiviral activity a s well as acceptable oral plasma concentrations in mice. Optimization of th ese properties led to four compounds as candidates for further evaluation. In view of the recognized potential for certain acetylenic drugs both to in hibit cytochrome P450 enzymes by mechanism-based inactivation and to possib ly perturb heme metabolism, information regarding drug effects on cytochrom es P450 and hepatic porphyrin levels was sought. In an initial single-dose pharmacokinetic study, the four selected compounds were given orally to mic e, 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 l evels. Analysis of plasma concentrations showed that only 4 and 5 gave sign ificant 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 dail y oral doses to mice. Upon completion of dosing, liver was analyzed for cyt ochrome P450-dependent 7-ethoxyresorufin O-deethylase (EROD) and benzphetam ine N-demethylase (BND) activities, total cytochrome P450 content, and porp hyrin levels. Both vinylacetylenes showed dose-dependent inhibitory and ind uction effects on EROD and END activities. In addition, these compounds cau sed a marked increase in hepatic porphyrin levels. Therefore, while all fou r selected compounds displayed potent antiviral activity and two of the com pounds exhibited acceptable pharmacokinetic properties, the hepatic effects of these latter two compounds suggest the potential for drug induced porph yria with multidose therapeutic use. (C) 1999 Published by Elsevier Science B.V. All rights reserved.