Direct assessment of peripheral pharmacokinetics in humans: comparison between cantharides blister fluid sampling, in vivo microdialysis and saliva sampling

Abstract

Aims: Skin blister fluid sampling, in vivo microdialysis and saliva sampling are commonly employed as surrogates for the measurement of drug concentrations in peripheral compartments. Although expected to exhibit comparable results, data derived from these techniques have never been directly compared. Thus, the aim of the present study was to evaluate the comparability of these techniques.

Methods: Paracetamol, a model drug with low protein binding, was administered to seven healthy volunteers at an oral dose of 2000 mg. Subsequently, tissue kinetics were measured simultaneously in cantharides induced skin blisters, microdialysates of subcutaneous- and skeletal muscle-tissue and saliva and compared to serum concentrations.

Results: Mean ratio (AUCblister/AUCserum) was 0.88 (95% CI, 0.50-1.26), mean ratio (AUCmuscle/AUCserum) was 1.08 (0.67-1.49), mean ratio (AUCsubcutaneous/AUCserum) was 0.96 (0.41-1.51) and mean ratio (AUCsaliva/AUCserum) was 1.83 (1.39-2.27). In this study the concentration profiles after single oral administration differed among the three methods. The time course of the concentration (peripheral compartment)/concentration (serum)-ratios showed that cantharides blister and microdialysate concentrations closely paralleled serum levels. An equilibration period of less than 2 h had to be taken into account for blister measurements. In contrast, saliva concentrations were significantly higher than corresponding serum concentrations.

Conclusions: Skin blister sampling and microdialysis closely mirrored corresponding serum concentrations and, thus, proved to be suitable techniques for the assessment of peripheral compartment pharmacokinetics. In contrast, saliva data overestimated the corresponding serum concentrations.

Figure 1

Time vs paracetamol concentration curves in cantharides blister fluid (○) (a; n = 5), saliva (□) (b; n = 6), muscle microdialysate (▵) (c; n = 6) and subcutaneous microdialysate (▿) (d; n = 6). For direct comparison, serum (▪) concentration curves obtained from the same volunteers are shown in each panel. Note that serum concentration curves may vary between panels since, for technical reasons, groups of volunteers were not identical. Results are presented as means±s.e. mean. 0 = time of administration.

Figure 2

Time course of the individual cantharides blister fluid/serum—(a), saliva/serum—(b), muscle microdialysate/serum—(c) and subcutaneous microdialysate/serum—(d) concentration ratios for paracetamol for the experiments shown in Figure 1. Results are presented as means±s.e. mean. 0 = time of administration.

Figure 3

Time courses of representative concentration curves for paracetamol: Time vs concentration curves for individual microdialysis experiments are depicted in the left panel. Individual time courses of paracetamol concentrations in saliva (□) and skin blister fluid (○) are shown in the right panel. (▪) Serum. Results are presented as absolute values. 0 = time of administration.