A STUDY TO DETERMINE THE PHARMACOKINETICS AND INFLAMMATORY FLUID PENETRATION OF 2 DOSES OF A SOLID FORMULATION OF THE HEXETIL PRODRUG OF A TRINEM, SANFETRINEM (GV-104326)

The trinem sanfetrinem (GV 104326) was administered as the oral hexeti l prodrug GV 118819X in two dose levels to six healthy volunteers, A s ingle dose equivalent to 125 mg of sanfetrinem was administered, follo wed 6 weeks later by a single dose equivalent to 500 mg of sanfetrinem . The concentrations of the drug in plasma, cantharidin-induced inflam matory fluid, and urine were measured with a microbiological assay, Th e stability of sanfetrinem was studied in serum and inflammatory fluid , The mean peak concentrations in plasma of 0.77 and 2.47 mu g/ml were attained at 1.1 and 2.0 h after the 125- and 500-mg doses, respective ly, Mean peak concentrations in inflammatory exudate of 0.26 and 0.86 mu g/ml were attained at 2.80 and 2.67 h after the 125- and 500-mg dos es, respectively, The mean terminal elimination half-lives in plasma w ere 1.33 and 1.97 h for the 125- and 500-mg doses, respectively. The h alf-lives in the inflammatory fluid were 1.66 and 1.74 h for the 125- and 500-mg doses, respectively, The overall penetration of the drug in to the inflammatory fluid was 51.4 and 47.0% for the 125- and 500-mg d oses, respectively, Mean urine recovery was greater following 500 mg ( 24.15%) than after 125 mg (18.4%) of sanfetrinem. Sanfetrinem was rela tively unstable in the inflammatory exudate in vitro (half-life, 5.5 h ), and this could explain the poor penetration of the drug in the infl ammatory exudate observed in this study.