Extravascular penetration of highly protein-bound flucloxacillin

Abstract

The pharmacokinetics of intravenously administered flucloxacillin (2.0 g to five volunteers) are described. The passage of flucloxacillin to peripheral lymph and suction skin blisters was monitored. This drug was selected because the high serum protein binding of 96% offered a particularly good opportunity for the study of the impact on tissue penetration. Flucloxacillin was assayed by high-pressure liquid chromatography, and pharmacokinetics were assayed by computerized curve fitting to accepted models. Penetration of flucloxacillin to extravascular foci was rapid, After 30 min the drug concentrations were 0.5 0.3 ,ug/ml in lymph and 0.9 -#-0.7 ,ug/ml in blister fluid. The peak concentration was 11.7 5.6 ,Ig/inl in lymph and 4.6 1.4 ,ug/ml in blister fluid. Concentrations in urine were above 111 + 50 ,Lg/ml throughout the 8-h monitoring period, and urinary recovery was 60.4%. The half-life was 2.1 + 0.9 h in serum, 1.4 + 0.6 h in lymph, and 11.0 + 4.1 h in blister fluid. The differences in half-life were significant (P < 0.05) between serum and blister fluid but not between lymph and serum. Penetration, as represented by the mean ratios of areas under the curve, was 19.7 8.1% to lymph and 38.2 11.7% to blister fluid. The flucloxacillin distribution volume during the phase of elimination was 36.4 + 16.0 liters and the total body clearance was 12.9 ±-5.5 liters. Flucloxacillin showed good tissue penetration, considering its very high serum protein binding. High flucloxacillin levels in lymph and blister fluid were explained in part by drug affinity to extravascular albumin. The major impacts of high protein binding are (i) slightly slower passage into extravascular sites, (ii) slightly later peak concentration, and (iii) levels in extravascular fluid that are persistently below those in serum.Very high serum protein binding reduces the fraction of molecules which can freely pass the vascular lining into tissues. We have studied the penetration into peripheral human lymph of a series of antibacterial agents with serum protein binding ranging from 0% (gentamicin) (3) to 85% (temocillin) (4). A distinct but not dramatic impact of the role of protein binding in reducing the extravascular penetration has been observed. Gentamicin shows overlapping levels in lymph and serum (3). Mecillinam with a 5% protein binding reaches lymph concentrations which are 97% of the levels in serum (7). The lymph concentrations of temocillin are 60% of the levels in serum (4). The last observation raises the question of whether a very high serum protein binding (above 80%) necessarily reduces extravascular penetration, as has been theoretically supported (8) and documented with cantharidine skin blisters (9).In this study we were concerned with the penetration of highly bound flucloxacillin, with 96% protein binding (1)

In Vivo Effect of Flucloxacillin in Experimental Endocarditis Caused by mecC -positive Staphylococcus aureus Showing Temperature-Dependent Susceptibility In Vitro

“…The half-life was ca. 1 h. These values were close to those reported in humans, i.e., 125 to 154 mg/liter, 14 mg/liter, 178.6 mg · h/liter, and 1 h, respectively (26,27). Flucloxacillin sterilized 80 to 100% of vegetations infected with mecC-MRSA strains and reduced the vegetation counts by Ͼ6 log10 CFU/g compared to those of controls (P Ͻ 0.005).…”

Application of mathematical model to experimental chemotherapy of fatal murine pneumonia

“…(14), and Shibl et al (15) and protein binding by Bergan et al (1), Dudley et al (3), and Wise et al (19). Furthermore, Craig and Ebert (2) studied the correlation of in vivo bacterial reduction with the area under the timeconcentration curve (AUJC), peak level, and other pharmacokinetic parameters to identify the major factors dominating efficacy.…”

Mass kinetics of apolipoprotein A-I in interstitial fluid after administration of intravenous apolipoprotein A-I/lecithin discs in humans

“…Engeset et al (18) described the appearance of radioiodinated albumin in leg lymph in eight cancer patients, but they did not model the data. Bergan et al (19) modeled the concentrations of antibiotics in human leg lymph, but only for 12 h. For our purposes, we needed to collect for a longer period.…”