Various sulfonamides and trimethoprim were given orally twice a day to healthy volunteers. The drug concentrations in serum and tissue fluid from skin blisters were determined concomitantly. Maximal serum concentrations were obtained after 1 to 3 h. Absorption of sulfacarbamide and sulfadimidine was more rapid than for sulfadiazine, sulfamethoxazole, and trimethoprim. The penetration to blister fluid was delayed and mimal concentrations were usually reached after 4 to 8 h. The highest penetration to blister fluid was found for sulfacarbamide, sulfadiazine, and trimethoprim. During maintenance therapy sulfadiazine and trimethoprim gave blister fluid concentrations usually above 50% of the serum level. However, on the basis of dosage the highest sulfonamide concentration both in serum and blister fluid was obtained with sulfamethoxazole.

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)

Toxicokinetic studies during hemodialysis are presented in two patients with blood ethylene glycol concentrations of 40 and 41 mmol/l, respectively. Treatment involved bicarbonate, ethanol and hemodialysis with a 1.6 m2 dialysator. Both patients developed acute renal failure and one was discharged with permanent cerebral impairment. The other made an uneventful recovery. The average dialysator clearance of ethylene glycol at a blood flow of 200 ml/min was 145 and 148 ml/min, respectively. Assuming a volume of distribution of ethylene glycol of 0.7 I/kg, the dialysator represented about 92 and 95%, respectively, of the total body clearance of ethylene glycol during ethanol treatment. During hernodialysis a blood ethanol concentration of about 15 mmol/l (0.7 g/l) caused a near complete inhibition of ethylene glycol metabolism at ethylene glycol concentrations up to about 25 Ihmol/l (1.6 g/l). We recommend prompt hemodialysis in ethylene glycol poisoning to supplement alkali and ethanol treatment.

The pharmacokinetics of methioprim have been studied in 11 healthy volunteers who received tablets of 320 mg as a first dose followed by 160 mg every 12 h. The concentrations were measured in plasma and skin blisters formed by suction, by high-pressure liquid chromatography. The mean individual peak concentrations during approximate steady state on the fourth day were 2.7 mg/l in serum and 1.3 mg/l in blister fluid. At steady state, 7.1 % of the dose was recovered in urine during the dosage interval of 12 h. The plasma half-life was the same after the first and final, steady state, dose with means ( ± SD) 9.29 ± 3.51 and 9.34 ± 2.19 h (NS). The substance was rapidly absorbed from the intestines with a rate constant of 2.345 ± 0.688 ^h––1. The rate constant of invasion into blister fluid after the first dose was 0.801 ± 0.164 ^h––1. The apparent lag time before gastrointestinal absorption was 0.29 h and before appearance in the blisters 1.23 h. The 12-hour area under the blister fluid curve was 39% of the plasma curve area after the first dose and 59% during steady state. The respective values for the time versus concentration curve until infinity were 63 and 99%.

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