A study to determine the pharmacokinetics and inflammatory fluid penetration of two 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 hexetil prodrug GV 118819X in two dose levels to six healthy volunteers. A single dose equivalent to 125 mg of sanfetrinem was administered, followed 6 weeks later by a single dose equivalent to 500 mg of sanfetrinem. The concentrations of the drug in plasma, cantharidin-induced inflammatory fluid, and urine were measured with a microbiological assay. The stability of sanfetrinem was studied in serum and inflammatory fluid. The mean peak concentrations in plasma of 0.77 and 2.47 microg/ml were attained at 1.1 and 2.0 h after the 125- and 500-mg doses, respectively. Mean peak concentrations in inflammatory exudate of 0.26 and 0.86 microg/ml were attained at 2.80 and 2.67 h after the 125- and 500-mg doses, respectively. The mean terminal elimination half-lives in plasma were 1.33 and 1.97 h for the 125- and 500-mg doses, respectively. The half-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 into the inflammatory fluid was 51.4 and 47.0% for the 125- and 500-mg doses, respectively. Mean urine recovery was greater following 500 mg (24.15%) than after 125 mg (18.4%) of sanfetrinem. Sanfetrinem was relatively unstable in the inflammatory exudate in vitro (half-life, 5.5 h), and this could explain the poor penetration of the drug in the inflammatory exudate observed in this study.
Wise
R
R
Department of Medical Microbiology, City Hospital NHS Trust, Birmingham, United Kingdom.
Andrews
J M
JM
Da Ros
L
L
Child
J
J
Mortiboy
D
D
D000284:Administration, Oral; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001768:Blister / Q000378:metabolism; D018592:Cross-Over Studies; D006801:Humans; D007769:Lactams; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D007769:Lactams; D011355:Prodrugs; C104757:sanfetrinem