10 healthy volunteers received 200 mg norfloxacin orally every 12 h for 7 days. Saliva, throat and faecal specimens were collected days 0, 3, 5, 7, 14 and 21 to study the effect of norfloxacin on the normal microflora. The concentrations of norfloxacin in serum, urine, saliva and faeces were determined by a microbiological method and all samples except faeces were also assayed by high-pressure liquid chromatography (HPLC). The pharmacokinetics of norfloxacin were studied on day 3. The mean peak serum concentration (+/- SD) attained after 0.75-1.0 h was 0.75 +/- 0.15 mg/l measured by HPLC, and the mean terminal serum half-life was 4.2 +/- 0.6 h. The mean cumulative urinary elimination was 29% during 12 h after dosing. There was no significant difference between values obtained by microbiological assay and by HPLC. The saliva concentration was approximately 30% of the serum levels 1.0-1.5 h after administration. No accumulation in faeces was found during the administration period, and mean concentrations were 940 mg/kg. The changes in the oropharyngeal flora were minor and only branhamella were affected. In the colonic flora, the number of enterobacteria was strongly depressed while the anaerobic microflora was only slightly affected. Two weeks after the administration period, both the oropharyngeal and colonic microflora had returned to normal.

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)

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A high-pressure-liquid chromatographic (HPLC) procedure for quantitative assay of cefotaxime (CT) and its major metabolite in serum of normal individuals, desacetyl cefotaxime (DACT), is described. It employs Lichrosorb RP-8, elution with phosphoric-acid-methanol and UV absorption at 310 nm. The method is optimized for cefotaxime and allows differentiation between the parent compound and the biotransformation product DACT. The lower assay sensitivity level of CT and DACT is 0.3 μg/ml. Correlation between HPLC and microbiological assay with Escherichia coli or Proteus rettgeri of pooled serum with CT added is r = 0.99. The method is rapid; processing of one sample takes 17 min. Use of HPLC avoids the errors of microbiological assays which derive from the presence in patient sera of different ratios of CT and DACT. The apparent rate of serum elimination is linearly related to the sensitivity of the microbial assay indicator strain to DACT. There is synergistic antibacterial activity between CT and DACT regardless of relative minimum inhibitory concentrations of the agents.

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